Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress

Maria Naama; 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; Shai Bel

doi:10.1016/j.chom.2023.01.006

Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress

Maria Naama, 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, Shai Bel

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	433-446.e4
Journal	Cell Host and Microbe
Volume	31
Issue number	3
DOIs	https://doi.org/10.1016/j.chom.2023.01.006
State	Published - 8 Mar 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Funding

This study was performed in memory of Beth Levine, a pioneer and a kind mentor. We thank Lora V. Hooper for donating samples from mice housed at UT Southwestern Medical Center. Funding: The Azrieli Foundation Early Career Faculty Fellowship (S.B.); Israel Science Foundation (ISF) grants 925/19 and 1851/19 (S.B.); European Crohn's and Colitis Organization (ECCO) grant (S.B.); Mizutani Foundation for Glycoscience (S.B.); European Research Council (ERC) starting grant GCMech 101039927 (S.B.); Swedish Research Council—grants 2018-02095 and 2021-06602 (B.O.S.), Conceptualization, M.N. M.W. B.O.S. M.N.-O. and S.B.; investigation, M.N. S.Telpaz, A.A. S.B.-S. S.H.-S. S.M. E.R. J.S. L.Z. M.Z. N.A. S.Turjeman, S.W. R.F. A.N. and M.N.-O.; funding acquisition, B.O.S. and S.B.; supervision, S.B.; writing – original draft, S.B.; writing – review & editing, M.W. B.O.S. S.Turjeman, M.N.-O. and S.B. The authors declare no competing interests. This study was performed in memory of Beth Levine, a pioneer and a kind mentor. We thank Lora V. Hooper for donating samples from mice housed at UT Southwestern Medical Center. Funding: The Azrieli Foundation Early Career Faculty Fellowship (S.B.); Israel Science Foundation (ISF) grants 925/19 and 1851/19 (S.B.); European Crohn’s and Colitis Organization (ECCO) grant (S.B.); Mizutani Foundation for Glycoscience (S.B.); European Research Council (ERC) starting grant GCMech 101039927 (S.B.); Swedish Research Council —grants 2018-02095 and 2021-06602 (B.O.S.)

Funders	Funder number
University of Texas Southwestern Medical Center
Mizutani Foundation for Glycoscience
European Crohn's and Colitis Organisation
European Commission	GCMech 101039927
Israel Science Foundation	1851/19, 925/19
Vetenskapsrådet	2021-06602, 2018-02095
Azrieli Foundation

Keywords

Beclin 1
ER stress
Nod2
autophagy
colitis
goblet cell
inflammatory bowel diseases
microbiota
mucus
unfolded protein response

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10.1016/j.chom.2023.01.006

Cite this

Naama, M., Telpaz, S., Awad, A., Ben-Simon, S., Harshuk-Shabso, S., Modilevsky, S., Rubin, E., Sawaed, J., Zelik, L., Zigdon, M., Asulin, N., Turjeman, S., Werbner, M., Wongkuna, S., Feeney, R., Schroeder, B. O., Nyska, A., Nuriel-Ohayon, M., & Bel, S. (2023). Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress. Cell Host and Microbe, 31(3), 433-446.e4. https://doi.org/10.1016/j.chom.2023.01.006

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title = "Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress",

abstract = "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.",

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Naama, M, Telpaz, S, Awad, A, Ben-Simon, S, Harshuk-Shabso, S, Modilevsky, S, Rubin, E, Sawaed, J, Zelik, L, Zigdon, M, Asulin, N, Turjeman, S, Werbner, M, Wongkuna, S, Feeney, R, Schroeder, BO, Nyska, A, Nuriel-Ohayon, M & Bel, S 2023, 'Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress', Cell Host and Microbe, vol. 31, no. 3, pp. 433-446.e4. https://doi.org/10.1016/j.chom.2023.01.006

TY - JOUR

T1 - Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress

AU - Naama, Maria

AU - Telpaz, Shahar

AU - Awad, Aya

AU - Ben-Simon, Shira

AU - Harshuk-Shabso, Sarina

AU - Modilevsky, Sonia

AU - Rubin, Elad

AU - Sawaed, Jasmin

AU - Zelik, Lilach

AU - Zigdon, Mor

AU - Asulin, Nofar

AU - Turjeman, Sondra

AU - Werbner, Michal

AU - Wongkuna, Supapit

AU - Feeney, Rachel

AU - Schroeder, Bjoern O.

AU - Nyska, Abraham

AU - Nuriel-Ohayon, Meital

AU - Bel, Shai

PY - 2023/3/8

Y1 - 2023/3/8

N2 - 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.

AB - 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.

KW - Beclin 1

KW - ER stress

KW - Nod2

KW - autophagy

KW - colitis

KW - goblet cell

KW - inflammatory bowel diseases

KW - microbiota

KW - mucus

KW - unfolded protein response

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C2 - 36738733

AN - SCOPUS:85149736929

SN - 1931-3128

VL - 31

SP - 433-446.e4

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 3

ER -

Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress

Abstract

Bibliographical note

Funding

Keywords

Access to Document

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