Mouse receptor interacting protein 3 does not contain a caspase-recruitingor a death domain but induces apoptosis and activates NF-kappa B

The death domain-containing receptor superfamily and their respective downs tream mediators control whether or not cells initiate apoptosis or activate NF-kappa B, events critical for proper immune system function. A screen fo r upstream activators of NF-kappa B identified a novel serine-threonine kin ase capable of activating NF-KB and inducing apoptosis, Based upon domain o rganization 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 mR IP3 contains neither motif and is unique. Despite this feature, overexpress ion of the mRIP3 C terminus is sufficient to induce apoptosis, suggesting t hat mRIP3 uses a novel mechanism to induce death. mRIP3 also induced NF-kap pa B activity which was inhibited by overexpression of either dominant-nega tive NIK or dominant-negative TRAF2. In vitro kinase assays demonstrate tha t mRIP3 is catalytically active and has autophosphorylation site(s) in the C-terminal domain, but the mRIP3 catalytic activity is not required for mRI P3 induced apoptosis and NF-kappa B activation. Unlike RIP and RIP2, mRIP3 mRNA is expressed in a subset of adult tissues and is thus likely to be a t issue-specific regulator of apoptosis and NF-kappa B activity, While the la ck of a dominant-negative mutant precludes linking mRIP3 to a known upstrea m regulator, characterizing the expression pattern and the in vitro functio ns of mRIP3 provides insight into the mechanism(s) by which cells modulate the balance between survival and death in a cell-type-specific manner.