Abstract

ABSTRACT/SUMMARYSensing of pathogens by Nucleotide oligomerization domain (NOD)-like 2 receptor (NOD2) induces a protective inflammatory response that coordinates bacterial clearance. Polymorphisms in NOD2 impair bacterial clearance, leading to chronic gut inflammation in Crohns disease (CD) via mechanisms that remain incompletely understood. We identify GIV/Girdin (CCDC88A) as a NOD2-interactor that shapes bacterial sensing-and-signaling in macrophages. Myeloid-specific GIV depletion exacerbated and protracted infectious colitis and abolished the protective effect of muramyl dipeptide (MDP) in both chemical colitis and severe sepsis. In the presence of GIV, macrophages enhance anti-bacterial pathways downstream of NOD2, clear microbes rapidly and concomitantly suppress inflammation. GIVs actions are mediated via its C-terminus, which directly binds the terminal leucine-rich repeat (LRR#10) of NOD2; binding is augmented by MDP and ATP, precedes receptor oligomerization, and is abolished by the 1007fs CD-risk variant which lacks LRR#10. Findings illuminate mechanisms that underlie protective NOD2 signaling and loss of function in the major 1007fs variant. In briefThis work reveals a mechanism by which macrophages use their innate immune sensor, NOD2, to protect the host against overzealous inflammation during bacterial infections, and the consequences of its loss, as occurs in the most important Crohns disease-risk variant. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/489574v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@139a1feorg.highwire.dtl.DTLVardef@ba5354org.highwire.dtl.DTLVardef@b4d933org.highwire.dtl.DTLVardef@11fe12e_HPS_FORMAT_FIGEXP M_FIG GRAPHIC ABSTRACT C_FIG HIGHLIGHTSO_LIGIV is a functional and direct interactor of the terminal LRR repeat of NOD2 C_LIO_LIMice lacking M[FE] GIV develop dysbiosis, protracted ileocolitis and sepsis C_LIO_LIMDP/NOD2-dependent protective host responses require GIV C_LIO_LICD-risk NOD2 1007fs variant lacking the terminal LRR#10 cannot bind GIV C_LI