Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.
Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. In cells homozygous for the Crohn's disease-associated NOD2 frameshift mutation, mutant Nod2 failed to recruit ATG16L1 to the plasma membrane and wrapping of invading bacteria by autophagosomes was impaired. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.
Travassos
Leonardo H
LH
Department of Immunology, University of Toronto, Toronto, Canada.
Carneiro
Leticia A M
LA
Ramjeet
Mahendrasingh
M
Hussey
Seamus
S
Kim
Yun-Gi
YG
Magalhães
João G
JG
Yuan
Linda
L
Soares
Fraser
F
Chea
Evelyn
E
Le Bourhis
Lionel
L
Boneca
Ivo G
IG
Allaoui
Abdelmounaaim
A
Jones
Nicola L
NL
Nuñez
Gabriel
G
Girardin
Stephen E
SE
Philpott
Dana J
DJ
D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001419:Bacteria / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism* / Q000382:microbiology / Q000648:ultrastructure; D002478:Cells, Cultured; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009154:Mutation; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C518959:ATG16L1 protein, human; C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D049452:Green Fluorescent Proteins