ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis

Abstract

The identification of inflammatory bowel disease (IBD) susceptibility genes by genome-wide association has linked this pathology to autophagy, a lysosomal degradation pathway that is crucial for cell and tissue homeostasis. Here, we describe autophagy-related 4B, cysteine peptidase/autophagin-1 (ATG4B) as an essential protein in the control of inflammatory response during experimental colitis. In this pathological condition, ATG4B protein levels increase in parallel with the induction of autophagy. Moreover, ATG4B expression is significantly reduced in affected areas of the colon from IBD patients. Consistently, atg4b (-/-) mice present Paneth cell abnormalities, as well as an increased susceptibility to DSS-induced colitis. atg4b-deficient mice exhibit significant alterations in proinflammatory cytokines and mediators of the immune response to bacterial infections, which are reminiscent of those found in patients with Crohn disease or ulcerative colitis. Additionally, antibiotic treatments and bone marrow transplantation from wild-type mice reduced colitis in atg4b (-/-) mice. Taken together, these results provided additional evidence for the importance of autophagy in intestinal pathologies and describe ATG4B as a novel protective protein in inflammatory colitis. Finally, we propose that atg4b-null mice are a suitable model for in vivo studies aimed at testing new therapeutic strategies for intestinal diseases associated with autophagy deficiency.

The functional and pathologic relevance of autophagy proteases

“…ATG4 mutations are also linked to some inflammatory bowel diseases (IBDs), as genetic variants in ATG4A and ATG4D have been proposed to contribute to granuloma formation in Crohn's disease (89). Additionally, patients with IBD show low expression of ATG4B in colon (77). These observations of altered ATG4 function in IBD are consistent with the fact that disrupted autophagy results in impaired processing of bacterial components, triggering the exacerbated inflammatory responses that characterize these disorders (90)(91)(92)(93)(94).…”

“…We have also found that mutant mice lacking ATG4B show altered secretion and assembly of otoconial components in the inner ear vestibular regions, ultimately leading to balance disorders (75,76). Moreover, Atg4b-deficient mice show impaired release of lysozyme granules in Paneth cells during dextran sodium sulfate-induced (DSS-induced) experimental colitis, resulting in exacerbated inflammation that leads to the death of these animals (77). This surprising role of ATG4B in protein secretion has also been described in bone resorption by osteoclasts (78), pointing to a novel function of autophagy in secretory cells (79) and further supporting the idea that ATG proteins are involved in non-canonical autophagic processes (80)(81)(82).…”

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

“…36,63,64 Here, we directly demonstrated aggravated experimental colitis in myeloid cell-specific autophagy-knockout mice, leading to increased mortality. In addition, we observed apparently increased colonic tissue expression of pro-Il1b and Il6 that are important players in colitis of DSS-treated Atg7 cKO mice compared to Atg7 cWT mice, [36][37][38] while the induction of Il6 was marginal.…”

The role of barrier function, autophagy, and cytokines in maintaining intestinal homeostasis

“…Notably, deletion of Atg5 in the intestinal epithelium also showed Paneth cell and granule abnormalities, while other IECs appeared to be normal [42]. Additionally, loss of Atg7 and Atg4B produces similar defects as ATG16L1 hypomorphic mice, leading to Paneth cell abnormalities, once again highlighting this cell type's sensitivity to autophagy disruption [55,56].…”