Autophagy-ER stress crosstalk controls mucus secretion and susceptibility to gut inflammation

Abstract

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.Abbreviations:BECN1- Beclin 1; ER- endoplasmic reticulum; UPR - unfolded protein response; NOD2 - nucleotide-binding oligomerization domain containing 2; IBD- inflammatory bowel disease; BCL2- B cell leukemia/lymphoma 2; TUDCA- tauroursodeoxycholic acid; ATG16L1- autophagy related 16 like 1; LRRK2- leucine-rich repeat kinase 2.

Keywords: Autophagy; BECN1; Crohn’s disease; ER stress; Goblet; Mucus.

Figure 1.

Autophagy facilitates mucus secretion from goblet cells. (A) Constitutive activation of autophagy in intestinal goblet cells leads to (B) reduction of ER stress levels, which facilitates (C) mucus secretion. This process depends on (i) the presence of the microbiota, which is likely (ii) sensed by the intracellular microbial sensor NOD2. Excess mucus secretion then results in (D) improved barrier function and reduces susceptibility to colitis. Created with BioRender.com.