ATG16L1: A multifunctional susceptibility factor in Crohn disease

Abstract

Genetic variations in the autophagic pathway influence genetic predispositions to Crohn disease. Autophagy, the major lysosomal pathway for degrading and recycling cytoplasmic material, constitutes an important homeostatic cellular process. Of interest, single-nucleotide polymorphisms in ATG16L1 (autophagy-related 16-like 1 [S. cerevisiae]), a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease. The most common and well-studied genetic variant of ATG16L1 (rs2241880; leading to a T300A conversion) exhibits a strong association with risk for developing Crohn disease. The rs2241880 variant plays a crucial role in pathogen clearance, resulting in imbalanced cytokine production, and is linked to other biological processes, such as the endoplasmic reticulum stress/unfolded protein response. In this review, we focus on the importance of ATG16L1 and its genetic variant (T300A) within the elementary biological processes linked to Crohn disease.

Keywords: ATG16L1; ATG16L1, autophagy-related 16-like 1 (S. cerevisiae); BCL2, B-cell CLL/lymphoma 2; Crohn disease; DCs, dendritic cells; ER, endoplasmic reticulum; GWAS, genome-wide association studies; IBD, inflammatory bowel disease; MDP, muramyl dipeptide; MTOR, mechanistic target of rapamycin; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B-cells; NOD2; NOD2, nucleotide-binding oligomerization domain containing 2; RIPK2, receptor-interacting serine-threonine kinase 2; SNP, single-nucleotide polymorphism; T300A, threonine-to-alanine substitution at amino acid position 300; TNF/TNF-α, tumor necrosis factor; UC, ulcerative colitis; ULK1, unc-51 like autophagy-activating kinase 1; XBP1, X-box binding protein 1; autophagy; bacterial clearance; endoplasmic reticulum stress.

Figure 1.

Schematic stages of the autophagic pathway. The process of autophagy progresses through several stages, including initiation, elongation, maturation, and degradation. Several stimuli are implicated in activation and inhibition of autophagy where the negative autophagic regulator; MTOR, is directly involved. Inhibition of MTOR, e.g., through nutrient starvation, rapamycin, or activation of AMP-activated protein kinase (AMPK) in energy-depleting conditions promotes autophagy. Activated AMPK inhibits also the MTOR downstream protein complex; the autophagic protein ULK1, which interacts with ATG13, ATG101 and RB1CC1. Conversely, nutrient-rich conditions deactivate MTOR and thereby suppress autophagy. Additionally, induction of the PI3K-AKT pathway by growth factors inhibits autophagy by activating MTOR and suppressing the BECN1-containing class III PtdIns3K complex. Activation of the ULK1 complex results in the translocation of the BECN1 complex to the assembly site of a phagophore and generates phosphatidylinositol-3-phosphate (PtdIns3P), which is involved in recruiting a number of ATG proteins. The BECN1 complex is activated by ATG14, SH3GLB1, UVRAG, and AMBRA1, and is suppressed by KIAA0226/Rubicon or BCL2. Elongation of the phagophore requires 2 ubiquitin-like conjugation systems, the ATG12–ATG5-ATG16L1 conjugation system and the microtubule-associated protein 1 light chain 3 (LC3) conjugation system. These conjugation systems require participation a range of proteases and ligases such as ATG3, ATG4B, ATG7, and ATG10 to trigger oligomerization on the outside of the membrane of the growing autophagosome. ATG9 and/or ATG16L1-positive vesicles are involved in membrane trafficking and formation of these autophagosomes. Under conditions of autophagosomal maturation, the ATG proteins are released back into the cytosol, and the final stages of autophagy can then be initiated by autophagosome-lysosome fusion using, for example, interaction between STX17, as an autophagosomal SNARE and its partners SNAP29 and VAMP8.

Figure 2.

The involvement of the T300A risk variant in the pathogenesis of Crohn disease. The schematic structure of ATG16L1 contains an N-terminal ATG5-binding region, and an amino-terminal coiled-coil domain (CCD; involved in self-dimerization) followed by 7 tryptophan-aspartic acid (WD40)-repeat domains. In the presence of the T300A variant, several cellular processes are affected. Among other things, defects in the morphology of the intestinal epithelium in key cells, including Paneth cells and goblet cells, are reported and the removal of pathogens is largely defective. In addition the T300A variant results in elevated endoplasmic reticulum stress, which plays a crucial role in impaired pathogen clearance and leads to imbalanced pro-inflammatory cytokines.