Mouse receptor interacting protein 3 does not contain a caspase-recruiting or a death domain but induces apoptosis and activates NF-kappaB.
The death domain-containing receptor superfamily and their respective downstream mediators control whether or not cells initiate apoptosis or activate NF-kappaB, events critical for proper immune system function. A screen for upstream activators of NF-kappaB identified a novel serine-threonine kinase capable of activating NF-kappaB and inducing apoptosis. Based upon domain organization and sequence similarity, this novel kinase, named mRIP3 (mouse receptor interacting protein 3), appears to be a new RIP family member. RIP, RIP2, and mRIP3 contain an N-terminal kinase domain that share 30 to 40% homology. In contrast to the C-terminal death domain found in RIP or the C-terminal caspase-recruiting domain found in RIP2, the C-terminal tail of mRIP3 contains neither motif and is unique. Despite this feature, overexpression of the mRIP3 C terminus is sufficient to induce apoptosis, suggesting that mRIP3 uses a novel mechanism to induce death. mRIP3 also induced NF-kappaB activity which was inhibited by overexpression of either dominant-negative NIK or dominant-negative TRAF2. In vitro kinase assays demonstrate that mRIP3 is catalytically active and has autophosphorylation site(s) in the C-terminal domain, but the mRIP3 catalytic activity is not required for mRIP3 induced apoptosis and NF-kappaB activation. Unlike RIP and RIP2, mRIP3 mRNA is expressed in a subset of adult tissues and is thus likely to be a tissue-specific regulator of apoptosis and NF-kappaB activity. While the lack of a dominant-negative mutant precludes linking mRIP3 to a known upstream regulator, characterizing the expression pattern and the in vitro functions of mRIP3 provides insight into the mechanism(s) by which cells modulate the balance between survival and death in a cell-type-specific manner.
Pazdernik
N J
NJ
Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Donner
D B
DB
Goebl
M G
MG
Harrington
M A
MA
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004249:DNA Damage; D053200:Fas-Associated Death Domain Protein; D015723:Gene Library; D017930:Genes, Reporter; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D017386:Sequence Homology, Amino Acid; D047992:TNF Receptor-Associated Factor 2; D000097782:NF-kappaB-Inducing Kinase
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D020169:Caspases; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D047992:TNF Receptor-Associated Factor 2; D000097782:NF-kappaB-Inducing Kinase; C505534:Fadd protein, mouse; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse