A Dual Role for Receptor-interacting Protein Kinase 2 (RIP2) Kinase Activity in Nucleotide-binding Oligomerization Domain 2 (NOD2)-dependent Autophagy. Homer, C. R., Kabi, A., Marina-Garcia, N., Sreekumar, A., Nesvizhskii, A. I., Nickerson, K. P., Chinnaiyan, A. M., Nunez, G., & McDonald, C. JOURNAL OF BIOLOGICAL CHEMISTRY, 287(30):25565-25576, JUL 20, 2012.
doi  abstract   bibtex   
Autophagy is triggered by the intracellular bacterial sensor NOD2 (nucleotide-binding, oligomerization domain 2) as an anti-bacterial response. Defects in autophagy have been implicated in Crohn's disease susceptibility. The molecular mechanisms of activation and regulation of this process by NOD2 are not well understood, with recent studies reporting conflicting requirements for RIP2 (receptor-interacting protein kinase 2) in autophagy induction. We examined the requirement of NOD2 signaling mediated by RIP2 for anti-bacterial autophagy induction and clearance of Salmonella typhimurium in the intestinal epithelial cell line HCT116. Our data demonstrate that NOD2 stimulates autophagy in a process dependent on RIP2 tyrosine kinase activity. Autophagy induction requires the activity of the mitogen-activated protein kinases MEKK4 and p38 but is independent of NF kappa B signaling. Activation of autophagy was inhibited by a PP2A phosphatase complex, which interacts with both NOD2 and RIP2. PP2A phosphatase activity inhibited NOD2-dependent autophagy but not activation of NF kappa B or p38. Upon stimulation of NOD2, the phosphatase activity of the PP2A complex is inhibited through tyrosine phosphorylation of the catalytic subunit in a process dependent on RIP2 activity. These findings demonstrate that RIP2 tyrosine kinase activity is not only required for NOD2-dependent autophagy but plays a dual role in this process. RIP2 both sends a positive autophagy signal through activation of p38 MAPK and relieves repression of autophagy mediated by the phosphatase PP2A.
@article{ ISI:000306651700064,
Author = {Homer, Craig R. and Kabi, Amrita and Marina-Garcia, Noemi and Sreekumar,
   Arun and Nesvizhskii, Alexey I. and Nickerson, Kourtney P. and
   Chinnaiyan, Arul M. and Nunez, Gabriel and McDonald, Christine},
Title = {{A Dual Role for Receptor-interacting Protein Kinase 2 (RIP2) Kinase
   Activity in Nucleotide-binding Oligomerization Domain 2 (NOD2)-dependent
   Autophagy}},
Journal = {{JOURNAL OF BIOLOGICAL CHEMISTRY}},
Year = {{2012}},
Volume = {{287}},
Number = {{30}},
Pages = {{25565-25576}},
Month = {{JUL 20}},
Abstract = {{Autophagy is triggered by the intracellular bacterial sensor NOD2
   (nucleotide-binding, oligomerization domain 2) as an anti-bacterial
   response. Defects in autophagy have been implicated in Crohn's disease
   susceptibility. The molecular mechanisms of activation and regulation of
   this process by NOD2 are not well understood, with recent studies
   reporting conflicting requirements for RIP2 (receptor-interacting
   protein kinase 2) in autophagy induction. We examined the requirement of
   NOD2 signaling mediated by RIP2 for anti-bacterial autophagy induction
   and clearance of Salmonella typhimurium in the intestinal epithelial
   cell line HCT116. Our data demonstrate that NOD2 stimulates autophagy in
   a process dependent on RIP2 tyrosine kinase activity. Autophagy
   induction requires the activity of the mitogen-activated protein kinases
   MEKK4 and p38 but is independent of NF kappa B signaling. Activation of
   autophagy was inhibited by a PP2A phosphatase complex, which interacts
   with both NOD2 and RIP2. PP2A phosphatase activity inhibited
   NOD2-dependent autophagy but not activation of NF kappa B or p38. Upon
   stimulation of NOD2, the phosphatase activity of the PP2A complex is
   inhibited through tyrosine phosphorylation of the catalytic subunit in a
   process dependent on RIP2 activity. These findings demonstrate that RIP2
   tyrosine kinase activity is not only required for NOD2-dependent
   autophagy but plays a dual role in this process. RIP2 both sends a
   positive autophagy signal through activation of p38 MAPK and relieves
   repression of autophagy mediated by the phosphatase PP2A.}},
DOI = {{10.1074/jbc.M111.326835}},
ISSN = {{0021-9258}},
ResearcherID-Numbers = {{Nesvizhskii, Alexey/A-5410-2012}},
Unique-ID = {{ISI:000306651700064}},
}

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