Differential involvement of Atg16L1 in Crohn disease and canonical autophagy: analysis of the organization of the Atg16L1 complex in fibroblasts.
A single nucleotide polymorphism in Atg16L1, an autophagy-related gene (ATG), is a risk factor for Crohn disease, a major form of chronic inflammatory bowel disease. However, it is still unknown how the Atg16L1 variant contributes to disease development. The Atg16L1 protein possesses a C-terminal WD repeat domain whose function is entirely unknown, and the Crohn disease-associated mutation (T300A) is within this domain. To elucidate the function of the WD repeat domain, we established an experimental system in which a WD repeat domain mutant of Atg16L1 is stably expressed in Atg16L1-deficient mouse embryonic fibroblasts. Using the system, we show that the Atg16L1 complex forms a dimeric complex and that the total Atg16L1 protein level is strictly maintained, possibly by the ubiquitin proteasome system. Furthermore, we show that an Atg16L1 WD repeat domain deletion and the T300A mutant have little impact on canonical autophagy and autophagy against Salmonella enterica serovar Typhimurium. Therefore, we propose that Atg16L1 T300A is differentially involved in Crohn disease and canonical autophagy.
Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Naonobu
N
Fujita
Tatsuya
T
Saitoh
Shun
S
Kageyama
Shizuo
S
Akira
Takeshi
T
Noda
Tamotsu
T
Yoshimori
D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002850:Chromatography, Gel; D003424:Crohn Disease / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D008957:Models, Genetic; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D017434:Protein Structure, Tertiary; D019779:Salmonella enterica / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry
C518959:ATG16L1 protein, human; C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex