The process by which T cells are activated, and the consequences of activation (e.g. new gene transcription, cytokine production, apoptosis), are being investigated by a variety of approaches: 1) TNF receptors are associated with two members of the IAP family (c-IAP1 and c-IAP2) as well as adaptor molecules such as TRAF2, which are necessary for signal transduction. We have found that upon TNF signaling TRAF2 is selectively ubiquitinated by c-IAP1 (which we have shown to be a ubiquitin protein ligase, or E3) and degraded in proteasomes. We have shown that this process requires the translocation of a c-IAP1/TRAF2 complex to the perinuclear ER, where c-IAP1 binds its cognate E2 and ubiquitinates TRAF2. How this is regulated in vivo, and the biological consequences thereof, is under investigation. 2) We have have found that in c-IAP1 knockout mice, c-IAP2 protein levels are markedly elevated in the absence of increased mRNA. Further analysis revealed that c-IAP2 is ubiquitinated by c-IAP1, and that this is responsible for the low levels of c-IAP2 found in most normal tissues. This result establishes that one E3 can constitutivelya and posttranscriptionally regulate the levels of another. 3) p38 is a MAP kinase (MAPK) involved in inflammatory processes. Like all MAPK, p38 is activated by Thr/Tyr dual phosphorylation via upstream MAP kinase kinases (MAPKK). We have found that T cells possess an alternative p38 activation pathway involving phosphorylation of a novel tyrosine residue in a MAPKK-independent manner. The mechanism and biological relevance of this alternative p38 activation pathway is being investigated. 4) GADD45a is a small adaptor protein involved in p38 and JNK activation. We have previously shown that mice deficient in this protein develop autoimmunity. We have now found that Gadd45a is a physiologic inhibitor of the p38 alternative activation pathway, and this MAPK is spontaneously active in Gadd45a-deficient T cells. Current studies involve analysis of how aberrant MAPK signaling in these mice relates to their immune phenotype.
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