The E3 ligase ARIH2 has an unusual structure and mechanism of elongating ubiquitin chains. To understand its physiological role, we generated gene-targeted mice deficient in ARIH2. ARIH2 deficiency resulted in the embryonic death of C57BL/6 mice. On a mixed genetic background, the lethality was attenuated, with some mice surviving beyond weaning and then succumbing to an aggressive multiorgan inflammatory response. We found that in dendritic cells (DCs), ARIH2 caused degradation of the inhibitor IκBβ in the nucleus, which abrogated its ability to sequester, protect and transcriptionally coactivate the transcription factor subunit p65 in the nucleus. Loss of ARIH2 caused dysregulated activation of the transcription factor NF-κB in DCs, which led to lethal activation of the immune system in ARIH2-sufficent mice reconstituted with ARIH2-deficient hematopoietic stem cells. Our data have therapeutic implications for targeting ARIH2 function.
MHC class I molecules present a comprehensive mixture of peptides on the cell surface for immune surveillance. The peptides represent the intracellular protein milieu produced by translation of endogenous mRNAs. Unexpectedly, the peptides are encoded not only in conventional AUG initiated translational reading frames but also in alternative cryptic reading frames. Here, we analyzed how ribosomes recognize and use cryptic initiation codons in the mRNA. We find that translation initiation complexes assemble at non-AUG codons but differ from canonical AUG initiation in response to specific inhibitors acting within the peptidyl transferase and decoding centers of the ribosome. Thus, cryptic translation at non-AUG start codons can utilize a distinct initiation mechanism which could be differentially regulated to provide peptides for immune surveillance.
Protein kinase C-associated kinase (PKK, also known as RIP4/DIK) activates NFB when overexpressed in cell lines and is required for keratinocyte differentiation in vivo. However, very little is understood about the factors upstream of PKK or how PKK activates NFB. Here we show that certain catalytically inactive mutants of PKK can activate NFB, although to a lesser degree than wild type PKK. The deletion of specific domains of wild type PKK diminishes the ability of this enzyme to activate NFB; the same deletions made on a catalytically inactive PKK background completely ablate NFB activation. PKK may be phosphorylated by two specific mitogen-activated protein kinase kinase kinases, MEKK2 and MEKK3, and this interaction may in part be mediated through a critical activation loop residue, Thr 184 . Catalytically inactive PKK mutants that block phorbol ester-induced NFB activation do not interfere with, but unexpectedly enhance, the activation of NFB by these two mitogen-activated protein kinase kinase kinases. Taken together, these data indicate that PKK may function in both a kinase-dependent as well as a kinaseindependent manner to activate NFB.Protein kinase C-associated kinase (PKK, 1 also known as RIP4/DIK) is an ankyrin repeat domain containing serine/threonine kinase that can activate NFB when expressed in cell lines (1, 2) and is required for keratinocyte differentiation in vivo (3). PKK was originally identified on the basis of its association with PKC (4) and PKC␦ (5) in yeast two-hybrid screens. Although PKC can phosphorylate PKK, there is no evidence for the catalytic activation of PKK by this or other PKCs (4).The kinase domain of PKK shares a high degree of homology with the catalytic domains of members of the receptor-interacting protein (RIP) family of protein kinases (1, 2). RIP is a death domain containing serine/threonine kinase that was first described as a consequence of its association with TNFR1 (tumor necrosis factor-␣ receptor 1) and FAS (CD95) (6, 7) and has since been shown to be recruited by TRADD (TNFR1-associated death domain protein) (6 -8) and TRAF2 (TNF receptor associated factor 2) (8) following TNF-␣ signaling. RIP has also been shown to associate with other TNFR family members such as RAIDD and DR3 (9, 10). Two other kinases, RIP2 and RIP3, were designated on the basis of the homology of their kinase domains to the corresponding domain of RIP, although other segments of these proteins are highly divergent. RIP2 (RICK/ CARDIAK) is a caspase-associated recruitment domain-containing kinase that associates with TNFR1 and the TRAF1, TRAF5, and TRAF6 adaptors (11). It has been implicated in Toll-like receptor signaling and has been shown to be important for both innate and adaptive immune responses (12, 13). The C terminus of RIP3 has no homology to any known functional domain, although this segment is critical for RIP3 to interact with and negatively regulate RIP (14).RIP, RIP2, and RIP3 have all been shown to both activate NFB and to induce apoptosis in a kinase-independent manner...
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