The Role of XIAP in Regulation of Apoptosis and Viral Replication in the Immune System.

Human X-linked inhibitor of apoptosis, or XIAP, is a member of the IAP family of proteins that has been shown to be a potent regulator of the cell death pathway, and has also been implicated as a mediator of other signal transduction pathways. Mutations in XIAP have been identified as a cause of X-linked lymphoproliferative disorder (XLP), a rare but fatal disease associated with aberrant response to Epstein-Barr virus (EBV). Surprisingly, mice that lack XIAP have not thus far been shown to have any major defects in apoptotic signaling, though JNK and NF-κB-dependent transcription have been implicated in defective responses to bacteria. The studies presented here show that XIAP is not a universal mediator of TGF-β signaling or NF-κB-dependent transcription. However, cells derived from Xiap-null mice exhibit increased sensitivity to apoptotic stimuli over their wildtype counterparts, but interestingly only under highly specific experimental conditions. A closely related family member, c-IAP2, is also shown to be protective from similar apoptotic stimuli, while another, c-IAP1, is not observed to protect cells from apoptosis. Our data also demonstrate that XIAP does not cause XLP in the same manner as another protein mutated in the same disease, SAP. Cells from Xiap-null mice respond differently to a murine γ-herpesvirus closely related to EBV, which may explain the role of XIAP in XLP. These studies will not only shed light on the function of XIAP in the regulation of the immune system, but will also help to understand the pathogenesis of XLP.Ph.D.ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/62362/1/jrumble_3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/62362/2/jrumble_1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/62362/3/jrumble_2.pd