Novel Functions of ATG16L1 in the Innate Response to Invasive Bacterial Pathogens

Crohnâ s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract. Susceptibility to CD is determined by both environmental and genetic risk factors. While the etiology of CD remains unclear, several pathways have been consistently implicated in susceptibility. Indeed, multiple genes involved in the innate immune response have been strongly linked to CD. Studies examining the function of these innate immune genes have indicated that an inability to properly handle bacteria that come into contact with the intestinal mucosa, as well as defects in the regulation of the inflammatory response triggered by innate recognition of these bacteria, are primary factors in increasing CD susceptibility. Autophagy, a degradation system for cytoplasmic cargo, has been implicated in both of these functions. ATG16L1 is a central component of the autophagy machinery and is a CD susceptibility locus. Here, two novel functions of ATG16L1 in the innate immune response are described. First, we uncovered a regulatory role for ATG16L1 in the inflammatory response driven by NOD1 and NOD2, which are intracellular sensors of bacterial invasion. Secondly, we identified an interaction between complement C3, the central component of the complement cascade, and ATG16L1. This interaction allows for efficient targeting of complement C3-coated invasive pathogens to the autophagy machinery. Both of these functions were impaired in cells expressing the CD-associated variant of ATG16L1. Overall, these findings indicate that dysfunction of ATG16L1 in both regulation of inflammation and defective handling of complement-coated intracellular bacteria might contribute to the generation of a harmful inflammatory state in the gastrointestinal tract.

Department dc:contributor.department

Immunology

Year dc:date.issued

2016

Author dc:creator

• Sorbara, Matthew Thomas

Advisor dc:contributor.advisor

• Philpott, Dana J

• ATG16L1
• Autophagy
• Infection
• NOD1
• NOD2

Handle dc:identifier.uri

http://hdl.handle.net/1807/89258

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/89258