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PREPRINTS

Antibiotics damage the colonic mucus barrier in a microbiota-independent manner

Jasmin Sawaed, Lilach Zelik, Yehonatan Levin, Rachel Feeney, Maria Naama, Ateret Gordon, Mor Zigdon, Elad Rubin, Shahar Telpaz, Sonia Modilevsky, Shira Ben-Simon, Aya Awad, Sarina Harshuk-Shabso, Meital Nuriel-Ohayon, Michal Werbner, Bjoern O Schroeder, Amir Erez, Shai Bel*. 2024. “Antibiotics damage the colonic mucus barrier in a microbiota-independent manner”. BioRxiv.
In Revision

Antibiotic use is a risk factor for development of inflammatory bowel diseases (IBDs). IBDs are characterized by a damaged mucus layer, which does not properly separate the host intestinal epithelium from the microbiota. Here, we hypothesized that antibiotics might affect the integrity of the mucus barrier. By systematically determining the effects of different antibiotics on mucus layer penetrability we found that oral antibiotic treatment led to breakdown of the mucus barrier and penetration of bacteria into the mucus layer. Using fecal microbiota transplant, RNA sequencing followed by machine learning and ex vivo mucus secretion measurements, we determined that antibiotic treatment induces ER stress in the colonic tissue which inhibits colonic mucus secretion in a microbiota-independent manner. This mucus secretion flaw led to penetration of bacteria into the colonic mucus layer, translocation of microbial antigens into circulation and exacerbation of ulcerations in a mouse model of IBD. Thus, antibiotic use might predispose to development of intestinal inflammation by impeding mucus production.

Abstract
PREPRINTS

Progesterone Supplementation in Mice Leads to Microbiome Alterations and Weight Gain in a Sex-Specific Manner

Nuriel-Ohayon, Meital, Sharon Komissarov, Meirav Ben Izhak, Oshrit Shtossel, Hadar Neuman, Oren Ziv, Sondra Turjeman, Shai Bel, Yoram Louzoun, and Omry Koren. 2021. “Progesterone Supplementation in Mice Leads to Microbiome Alterations and Weight Gain in a Sex-Specific Manner.” BioRxiv.
In Revision

Background Progesterone is a steroid hormone produced by the ovaries, involved in pregnancy progression and necessary for successful gestation. We have previously shown that progesterone affects gut microbiota composition and leads to increased relative abundance of Bifidobacterium.

Results In non-pregnant female GF mice, levels of progesterone were significantly higher than in SPF mice of the same status. However, no significant differences were observed between GF and SPF males. Females treated with progesterone gained more weight than females treated with a placebo. In contrast to female mice, males treated with progesterone did not gain significantly more weight than males treated with a placebo. Progesterone supplementation led to microbial changes in females but not in males (16S rRNA sequencing). Accordingly, the weight gain observed in female mice treated with progesterone was fully transferable to both male and female germ-free mice via fecal transplantation.

Conclusions We demonstrate that bacteria play a role in regulating progesterone levels in a female-specific manner. Furthermore, weight gain and metabolic changes associated with progesterone may be mediated by the gut microbiota.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Optimal antimicrobial response to a changing microbial background at a mucus interface

Bossa, Guilherme Volpe, Shai Bel, Andrew Mugler, and Amir Erez. 2024. “Optimal antimicrobial response to a changing microbial background at a mucus interface.” Physical Review Research 6, 023027 – Published 5 April 2024.

Complex lifeforms host microbiota, microbes that live synergistically with their host. Accordingly, hosts have mechanisms to defend against and tolerate the microbiota. The intestinal mucus, where these systems collide, plays a pivotal role in managing this relationship, yet lacks an integrative theoretical framework. We propose a minimal model to elucidate dynamics at this interface, focusing on the ileum’s mucus defense.
The model considers the effect of delay in host antimicrobial peptide secretion and how the host can use two different signals, from the bulk microbiota and from segmented filamentous bacteria (SFB), assuming that the SFB anticipate the bulk microbiota. We propose a theory whereby the host can optimize defense by minimizing antimicrobial peptide production and controlling bacterial exposure. Integrating two recent experiments, we show host dynamics are consistent with sensing both bulk and SFB, supporting our “optimal defense” hypothesis. Therefore, we propose that similar mechanisms could prove advantageous to other species and applicable beyond the ileum’s mucus barrier.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β

Zigdon M, Sawaed J, Zelik L, Binyamin D, Ben-Simon S, Asulin N, Levin R, Modilevsky S, Naama M, Telpaz S, Rubin E, Awad A, Sawaed W, Harshuk-Shabso S, Nuriel-Ohayon M, Krishnamohan M, Werbner M, Koren O, Winter SE, Apte RN, Voronov E, Bel S*. 2024 “Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β”. PLoS Biology. Jan 18;22(1):e3002486.

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1β production is detrimental during Salmonella infection. Mice lacking IL-1β (IL-1β -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid (SCFA)-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1β -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1β induces expression of complement anaphylatoxins and suppresses the complement-inactivator carboxypeptidase N (CPN1). Disrupting this process via IL-1β loss prevented mortality in Salmonella-infected IL-1β -/- mice. Finally, we found that IL-1β expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1β signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1β signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Autophagy-ER Stress Crosstalk Controls Mucus Secretion and Susceptibility to Gut Inflammation

Naama, Maria, and Shai Bel*. 2023. “Autophagy-ER Stress Crosstalk Controls Mucus Secretion and Susceptibility to Gut Inflammation.” Autophagy 19(11):3014–16.

Mucus secretion from colonic goblet cells is an important host defense mechanism against the harsh lumenal environment. Yet how mucus secretion is regulated is not well understood. We discovered that constitutive activation of macroautophagy/autophagy via BECN1 (beclin 1) relieves endoplasmic reticulum (ER) stress in goblet cells, which in turn produce a thicker and less penetrable mucus barrier. Pharmacological reduction of the ER stress or activation of the unfolded protein response (UPR) in mice, regardless of autophagy activation, lead to excess mucus secretion. This regulation of mucus secretion by ER stress is microbiota-dependent and requires the activity of the intracellular sensor NOD2 (nucleotide-binding oligomerization domain containing 2). Excess mucus production in the colon alters the gut microbiota and protects from chemical- and infection-driven inflammation. Our findings provide new insights into the mechanisms by which autophagy regulates mucus secretion and susceptibility to intestinal inflammation.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

CHD8 Regulates Gut Epithelial Cell Function and Affects Autism-Related Behaviors through the Gut-Brain Axis

Chatterjee, Ipsita, Dmitriy Getselter, Nasreen Ghanayem, Ram Harari, Liron Davis, Shai Bel, and Evan Elliott. 2023. “CHD8 Regulates Gut Epithelial Cell Function and Affects Autism-Related Behaviors through the Gut-Brain Axis.” Translational Psychiatry 13(1):305.

Autism is a neurodevelopmental disorder characterized by early-onset social behavioral deficits and repetitive behaviors. Chromodomain helicase DNA-binding protein (CHD8) is among the genes most strongly associated with autism. In addition to the core behavioral symptoms of autism, affected individuals frequently present with gastrointestinal symptoms that are also common among individuals harboring mutations in the gene encoding CHD8. However, little is known regarding the mechanisms whereby CHD8 affects gut function. In addition, it remains unknown whether gastrointestinal manifestations contribute to the behavioral phenotypes of autism. The current study found that mice haploinsufficient for the large isoform of Chd8 (Chd8L) exhibited increased intestinal permeability, transcriptomic dysregulation in gut epithelial cells, reduced tuft cell and goblet cell counts in the gut, and an overall increase in microbial load. Gut epithelial cell-specific Chd8 haploinsufficiency was associated with increased anxiety-related behaviors together with a decrease in tuft cell numbers. Antibiotic treatment of Chd8L haploinsufficient mice attenuated social behavioral deficits. Together, these results suggest Chd8 as a key determinant of autism-related gastrointestinal deficits, while also laying the ground for future studies on the link between GI deficits and autism-related behaviors.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Autophagy in Intestinal Epithelial Cells Prevents Gut Inflammation

Telpaz, Shahar, and Shai Bel*. 2023. “Autophagy in Intestinal Epithelial Cells Prevents Gut Inflammation.” Trends in Cell Biology 33(10):817–19.

Intestinal epithelial cells form the largest barrier in the body, separating us from the outside world. Here, we review recent findings that highlight the role of autophagy in the cell-intrinsic response of the epithelial cells to the harsh intestinal environment and how they shape host physiology.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Autophagy Controls Mucus Secretion from Intestinal Goblet Cells by Alleviating ER Stress

Naama, Maria, Shahar Telpaz, Aya Awad, Shira Ben-Simon, Sarina Harshuk-Shabso, Sonia Modilevsky, Elad Rubin, Jasmin Sawaed, Lilach Zelik, Mor Zigdon, Nofar Asulin, Sondra Turjeman, Michal Werbner, Supapit Wongkuna, Rachel Feeney, Bjoern O. Schroeder, Abraham Nyska, Meital Nuriel-Ohayon, and Shai Bel*. 2023. “Autophagy Controls Mucus Secretion from Intestinal Goblet Cells by Alleviating ER Stress.” Cell Host & Microbe 31(3):433-446.e4. doi: 10.1016/j.chom.2023.01.006.
#Highlighted in Nature Reviews Gastroenterology & Hepatology, Science Signaling and Cell Host & Microbe.

Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn’s-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Diet-Induced Modifications to Human Microbiome Reshape Colonic Homeostasis in Irritable Bowel Syndrome

Bootz-Maoz, Hadar, Ayelet Pearl, Ehud Melzer, Stephen Malnick, Efrat Sharon, Yifat Bennet, Rotem Tsentsarevsky, Shlomi Abuchatzera, Sivan Amidror, Elana Aretz, Shalhevet Azriel, Chen Gam Ze Letova, Maria Naama, Irit Shoval, Orly Yaron, Sarit Karako-Lampert, Shai Bel, and Nissan Yissachar. 2022. “Diet-Induced Modifications to Human Microbiome Reshape Colonic Homeostasis in Irritable Bowel Syndrome.” Cell Reports 41(7):111657.

Changes in microbiome composition are associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet, clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we infuse gut organ cultures with longitudinal microbiota samples collected from therapy-naive patients with irritable bowel syndrome (IBS) under a low-fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a pathway discovery platform for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of a low-FODMAP diet and reinforce the potential feasibility of microbiome-based therapies in IBS.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

A Staphylococcus Path to Improved Therapeutics in Atopic Dermatitis

Harris-Tryon, Tamia A., and Shai Bel*. 2021. “A Staphylococcus Path to Improved Therapeutics in Atopic Dermatitis.” JAMA Dermatology 157(8):909–10. 10.1001/jamadermatol.2021.1310

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (4th Edition)1.

Klionsky, Daniel J., et al. 2021. “Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (4th Edition)1.” Autophagy 17(1):1–382. doi: 10.1080/15548627.2020.1797280.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Lysozyme: A Double-Edged Sword in the Intestine

Zigdon, Mor, and Shai Bel*. 2020. “Lysozyme: A Double-Edged Sword in the Intestine.” Trends in Immunology 41(12):1054–56.

Lysozyme-secreting Paneth cells are abnormally present in the distal colons of patients with inflammatory bowel disease (IBD), along with high amounts of lysozyme in feces. In a recent article in Immunity, Yu et al. show that lysozyme-mediated processing of luminal bacteria in the colon triggers a proinflammatory response and predisposes mice to experimental IBD.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Resistin-like Molecule α Provides Vitamin-A-Dependent Antimicrobial Protection in the Skin

Harris, Tamia A., Sureka Gattu, Daniel C. Propheter, Zheng Kuang, Shai Bel, Kelly A. Ruhn, Andrew L. Chara, Marshall Edwards, Chenlu Zhang, Jay-Hyun Hyun Jo, Prithvi Raj, Christos C. Zouboulis, Heidi H. Kong, Julia A. Segre, and Lora V. Hooper. 2019. “Resistin-like Molecule α Provides Vitamin-A-Dependent Antimicrobial Protection in the Skin.” Cell Host & Microbe 25(6):777-788.e8.

Vitamin A deficiency increases susceptibility to skin infection. However, the mechanisms by which vitamin A regulates skin immunity remain unclear. Here, we show that resistin-like molecule α (RELMα), a small secreted cysteine-rich protein, is expressed by epidermal keratinocytes and sebocytes and serves as an antimicrobial protein that is required for vitamin-A-dependent resistance to skin infection. RELMα was induced by microbiota colonization of the murine skin, was bactericidal in vitro, and was protected against bacterial infection of the skin in vivo. RELMα expression required dietary vitamin A and was induced by the therapeutic vitamin A analog isotretinoin, which protected against skin infection in a RELMα-dependent manner. The RELM family member Resistin was expressed in human skin, was induced by vitamin A analogs, and killed skin bacteria, indicating a conserved function for RELM proteins in skin innate immunity. Our findings provide insight into how vitamin A promotes resistance to skin infection.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Secretory Autophagy of Lysozyme in Paneth Cells

Bel, Shai*, and Lora V. Hooper. 2018. “Secretory Autophagy of Lysozyme in Paneth Cells.” Autophagy 14(4):719–21. doi: 10.1080/15548627.2018.1430462.

Secretion of antimicrobial proteins is an important host defense mechanism against bacteria, yet how secretory cells maintain function during bacterial invasion has been unclear. We discovered that Paneth cells, specialized secretory cells in the small intestine, react to bacterial invasion by rerouting a critical secreted antibacterial protein through a macroautophagy/autophagy-based secretion system termed secretory autophagy. Mice harboring a mutation in an essential autophagy gene, a mutation which is common in Crohn disease patients, cannot reroute their antimicrobial cargo during bacterial invasion and thus have compromised innate immunity. We showed that this alternative secretion system is triggered by both a cell-intrinsic mechanism, involving the ER stress response, and a cell-extrinsic mechanism, involving subepithelial innate immune cells. Our findings uncover a new role for secretory autophagy in host defense and suggest how a mutation in an autophagy gene can predispose individuals to Crohn disease.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Paneth Cells Secrete Lysozyme via Secretory Autophagy during Bacterial Infection of the Intestine

Bel, Shai, Mihir Pendse, Yuhao Wang, Yun Li, Kelly A. K. A. Ruhn, Brian Hassell, Tess Leal, Sebastian E. S. E. Winter, Ramnik J. R. J. Ramnik J. Xavier, and Lora V. L. V. Hooper. 2017. “Paneth Cells Secrete Lysozyme via Secretory Autophagy during Bacterial Infection of the Intestine.” Science 357(6355):eaal4677.
#Highlighted in Science Signaling, Nature Reviews Gastroenterology & Hepatology, Nature Reviews Immunology, Autophagy and Science.

Intestinal Paneth cells limit bacterial invasion by secreting antimicrobial proteins, including lysozyme. However, invasive pathogens can disrupt the Golgi apparatus, interfering with secretion and compromising intestinal antimicrobial defense. Here we show that during bacterial infection, lysozyme is rerouted via secretory autophagy, an autophagy-based alternative secretion pathway. Secretory autophagy was triggered in Paneth cells by bacteria-induced endoplasmic reticulum (ER) stress, required extrinsic signals from innate lymphoid cells, and limited bacterial dissemination. Secretory autophagy was disrupted in Paneth cells of mice harboring a mutation in autophagy gene Atg16L1 that confers increased risk for Crohn’s disease in humans. Our findings identify a role for secretory autophagy in intestinal defense and suggest why Crohn’s disease is associated with genetic mutations that affect both the ER stress response and autophagy.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

TMF/ARA160 Governs the Dynamic Spatial Orientation of the Golgi Apparatus during Sperm Development

Elkis, Yoav, Shai Bel, Roni Rahimi, Tali Lerer-Goldstein, Smadar Levin-Zaidman, Tatiana Babushkin, Sally Shpungin, and Uri Nir. 2015. “TMF/ARA160 Governs the Dynamic Spatial Orientation of the Golgi Apparatus during Sperm Development.” PLoS ONE 10(12).

 

TMF/ARA160 is known to be a TATA element Modulatory Factor (TMF). It was initially identified as a DNA-binding factor and a coactivator of the Androgen receptor. It was also characterized as a Golgi-associated protein, which is essential for acrosome formation during functional sperm development. However, the molecular roles of TMF in this intricate process have not been revealed. Here, we show that during spermiogenesis, TMF undergoes a dynamic change of localization throughout the Golgi apparatus. Specifically, TMF translocates from the cis-Golgi to the trans-Golgi network and to the emerging vesicles surface, as the round spermatids develop. Notably, lack of TMF led to an abnormal spatial orientation of the Golgi and to the deviation of the trans-Golgi surface away from the nucleus of the developing round spermatids. Concomitantly, pro-acrosomal vesicles derived from the TMF-/- Golgi lacked targeting properties and did not tether to the spermatid nuclear membrane thereby failing to form the acrosome anchoring scaffold, the acroplaxome, around the cell-nucleus. Absence of TMF also perturbed the positioning of microtubules, which normally lie in proximity to the Golgi and are important for maintaining Golgi spatial orientation and dynamics and for chromatoid body formation, which is impaired in TMF-/- spermatids. In-silico evaluation combined with molecular and electron microscopic analyses revealed the presence of a microtubule interacting domain (MIT) in TMF, and confirmed the association of TMF with microtubules in spermatogenic cells. Furthermore, the MIT domain in TMF, along with microtubules integrity, are required for stable association of TMF with the Golgi apparatus. Collectively, we show here for the first time that a Golgi and microtubules associated protein is crucial for maintaining proper Golgi orientation during a cell developmental process.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

A Bacterial Nudge to T-Cell Function

Bel, Shai, and Lora V. Hooper. 2015. “A Bacterial Nudge to T-Cell Function.” Nature 526(7573):328–30.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Reprogrammed and Transmissible Intestinal Microbiota Confer Diminished Susceptibility to Induced Colitis in TMF-/- Mice

Bel, Shai, Yoav Elkis, Hila Elifantz, Omry Koren, Rotem Ben-Hamo, Tal Lerer-Goldshtein, Roni Rahimi, Shomron Ben Horin, Abraham Nyska, Sally Shpungin, and Uri Nir. 2014. “Reprogrammed and Transmissible Intestinal Microbiota Confer Diminished Susceptibility to Induced Colitis in TMF-/- Mice.” Proceedings of the National Academy of Sciences of the United States of America 111(13):4964–69.

 

Tata Element Modulatory Factor (TMF/ARA160) is a multifunctional Golgi-associated protein, which accumulates in colonic enterocytes and goblet cells. Mice lacking TMF/ARA160 (TMF(-/-)) produce thick and uniform colonic mucus that resists adherent bacterial colonization and diminishes susceptibility of these mice to induced acute colitis, through a mechanism that is not fully understood. Here, we show that mucus secretion by goblet cells is altered in the colon of TMF(-/-) mice, resulting in the formation of a highly oligomerized colonic gel-forming mucin, MUC2. Microbiome analysis revealed a shift in the microbiota of TMF(-/-) mice leading to predominance of the Firmicutes phylum and a significantly higher abundance of probiotic beneficial bacterial species. Notably, this trait was transmissible, and when cohoused with wild-type animals, TMF(-/-) mice influenced the microbiota and diminished the susceptibility of wild-type mice to chemically induced dextran sulfate sodium colitis. Thus, altered mucus secretion in TMF(-/-) mouse colons is accompanied by a reprogrammed intestinal microbiota, leading to a transmissible reduced sensitivity to induced colitis.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Testosterone Deficiency Accompanied by Testicular and Epididymal Abnormalities in TMF-/- Mice

Elkis, Yoav, Shai Bel, Tali Lerer-Goldstein, Abraham Nyska, Dianne M. Creasy, Sally Shpungin, and Uri Nir. 2013. “Testosterone Deficiency Accompanied by Testicular and Epididymal Abnormalities in TMF-/- Mice.” Molecular and Cellular Endocrinology 365(1):52–63. doi: 10.1016/j.mce.2012.09.003.

 

TMF/ARA160 is a Golgi-associated protein, which is essential for spermiogenesis. In this study, we show that lack of TMF/ARA160 leads to defects in both the testis and the epididymis. In the testis, spermatid retention and extensive proliferation of Leydig cells were observed. Concomitantly, the serum levels of luteinizing hormone (LH), a stimulator of Leydig cell proliferation, were significantly increased in TMF(-/-) mice. Structural and functional defects were also seen in the epididymis. These included apoptosis of epithelial epididymal cells and sperm stasis in the cauda. Notably, the serum testosterone levels of TMF(-/-) mice were significantly lower than those of wt mice, and external testosterone administration decreased the number of apoptotic epithelial epididymal cells in TMF(-/-) animals. In summary, we show here for the first time that TMF/ARA160 participates in the control of serum testosterone levels in males, and its absence results in major testicular and epididymal defects.

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

Loss of TMF/ARA160 Protein Renders Colonic Mucus Refractory to Bacterial Colonization and Diminishes Intestinal Susceptibility to Acute Colitis

Bel, Shai, Yoav Elkis, Tali Lerer-Goldstein, Abraham Nyska, Sally Shpungin, and Uri Nir. 2012. “Loss of TMF/ARA160 Protein Renders Colonic Mucus Refractory to Bacterial Colonization and Diminishes Intestinal Susceptibility to Acute Colitis.” Journal of Biological Chemistry 287(30):25631–39.

TMF/ARA160 is a Golgi-associated protein with several cellular functions, among them direction of the NF-κB subunit, p65 RelA, to ubiquitination and proteasomal degradation in stressed cells. We sought to investigate the role of TMF/ARA160 under imposed stress conditions in vivo. TMF(-/-) and wild-type (WT) mice were treated with the ulcerative agent dextran sulfate sodium (DSS), and the severity of the inflicted acute colitis was determined. TMF(-/-) mice were found to be significantly less susceptible to DSS-induced colitis, with profoundly less bacterial penetration into the colonic epithelia. Surprisingly, unlike in WT mice, no bacterial colonies were visualized in colons of healthy untreated TMF(-/-) mice, indicating the constitutive resistance of TMF(-/-) colonic mucus to bacterial retention and penetration. Gene expression analysis of colon tissues from unchallenged TMF(-/-) mice revealed 5-fold elevated transcription of the muc2 gene, which encodes the major component of the colonic mucus gel, the MUC2 mucin. Accordingly, the morphology of the colonic mucus in TMF(-/-) mice was found to differ from the mucus structure in WT colons. The NF-κB subunit, p65, a well known transcription inducer of muc2, was up-regulated significantly in TMF(-/-) intestinal epithelial cells. However, this did not cause spontaneous inflammation or increased colonic crypt cell proliferation. Collectively, our findings demonstrate that absence of TMF/ARA160 renders the colonic mucus refractory to bacterial colonization and the large intestine less susceptible to the onset of colitis.

 

Abstract
PEER-REVIEWED JOURNAL PUBLICATIONS

TMF/ARA160: A Key Regulator of Sperm Development

Lerer-Goldshtein, Tal, Shai Bel, Sally Shpungin, Erez Pery, Benny Motro, Ronald S. Goldstein, Sarit Itach Bar-Sheshet, Haim Breitbart, and Uri Nir. 2010. “TMF/ARA160: A Key Regulator of Sperm Development.” Developmental Biology 348(1):12–21.

 

TMF/ARA160 is a Golgi-associated protein to which several cellular activities have been attributed. These include, trafficking of Golgi-derived vesicles and E3 ubiquitin ligase activity. Here we show that TMF/ARA160 is required for the onset of key processes which underlie the development of mature sperm in mammals. TMF/ARA160 is highly expressed in specific spermatogenic stages. While the protein is not detected in the spermatogenic progenitor cells – spermatogonia, it accumulates in the Golgi of spermatocytes and spermatids but then disappears and is absent from spermatozoa and epididymal sperm cells. Mice that are homozygous null for TMF develop normally are healthy and the females are fertile. However, the males are sterile and their spermatids suffer from several developmental defects. They lack homing of Golgi-derived proacrosomal vesicles to the perinuclear surface, resulting in spermatozoa and epididymal sperm cells which lack acrosome. In a later developmental stage, the cytoplasm is not properly removed, thus resulting in spermatids which bare the nucleus with tightly packed DNA, surrounded by a cytoplasm. Finally, the spermatozoa of TMF(-/-) mice also suffer from misshapen heads, tails coiling around the sperm heads, and lack of motility. Taken together our findings portray TMF/ARA160 as a key regulator which is essential for the onset of key events in the differentiation and maturation of mammalian sperm and whose absence severely compromises their ability to fertilize ova.

Abstract
BOOK CHAPTERS

Goblet and Paneth Cells: Producers of the Intestinal Barrier.

Modilevsky, Sonia, Maria Naama, and Shai Bel*. 2023. “Goblet and Paneth Cells: Producers of the Intestinal Barrier.” Pp. 66–71 in Encyclopedia of Cell Biology (Second Edition).
Oxford: Academic Press.

Abstract
BOOK CHAPTERS

Chapter 19 – Antimicrobial Peptides and the Skin and Gut Microbiomes

Joseph, Adrienne, Meital Nuriel-Ohayon, Shai Bel*, and Tamia A. Harris. 2022. “Chapter 19 – Antimicrobial Peptides and the Skin and Gut Microbiomes.”
Pp. 439–56 in
Peptide and Peptidomimetic Therapeutics, edited by N. Qvit and S. J. S. Rubin. Academic Press.

Abstract
BOOK CHAPTERS

Gene/Environment Interaction and Autoimmune Disease

Harris-Tryon, Tamia A., and Shai Bel*. 2020. “Gene/Environment Interaction and Autoimmune Disease.”
Pp. 139–56 in
Beyond Our Genes: Pathophysiology of Gene and Environment Interaction and Epigenetic Inheritance. Cham: Springer International Publishing.

Abstract

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