PDF《Autophagy》

T;

nucleotide substitution from C to T) is in strong linkage disequilibrium (r2 = 1) with a deleted allele of a

20 kb copy number variation upstream of IRGM. The copy number variation deletion allele correlates with differential expression of IRGM in culture cells. A reduction in the IRGM expression is associated with an impairment in the induction of autophagy and the clearance of intracellular pathogens.11 In addition, Brest et al. show that the IRGM c.313C >

T polymorphism alters a miRNA binding site, controlling the levels of IRGM. Since, at least three more genes implicated in autophagy have been linked with CD. The meta-analysis from Barrett et al. has identified LRRK2 (rs11175593).1 LRRK2 is expressed in immune cells and in the mucosa of patients with CD.12 A recent study shows its negative regulation of the autophagy process: silencing of LRRK2 resulted in increased autophagic activity.13 Two GWAS performed in early-onset disease have identified the MTMR3 gene (rs2412973),14 which has been confirmed in the second CD meta-analysis.2 MTMR3 plays a role in autophagosome formation.14 Finally, our group has described a genetic association between ULK1 (rs12303764), essential for autophagy initiation, and CD in two independent cohorts.15 The third CD-associated pathway is ER stress signaling.16 A correct response to ER stress allows cells to cope with excessive amounts of misfolded/unfolded proteins via a complex signaling network called '

the unfolded protein response'

(UPR). ER stress is increased in inflamed intestinal epithel........