First Author | Giardino Torchia ML | Year | 2013 |
Journal | PLoS One | Volume | 8 |
Issue | 6 | Pages | e66161 |
PubMed ID | 23799077 | Mgi Jnum | J:199221 |
Mgi Id | MGI:5501254 | Doi | 10.1371/journal.pone.0066161 |
Citation | Giardino Torchia ML, et al. (2013) c-IAP1 and c-IAP2 Redundancy Differs between T and B Cells. PLoS One 8(6):e66161 |
abstractText | Cellular Inhibitors of Apoptosis 1 and 2 (c-IAP1 and c-IAP2) are ubiquitin protein ligases (E3s) that constitutively ubiquitinate and induce proteasomal-mediated degradation of NF-kappaB Inducing Kinase (NIK) and repress non-canonical NF-kappaB activation. Mice expressing an E3-inactive c-IAP2 mutant (c-IAP2(H570A)) have constitutive activation of non-canonical NF-kappaB, resulting in B cell hyperplasia and T cell costimulation-independence. If, and if so to what extent, c-IAP1 and c-IAP2 are redundant in NF-kappaB regulation in these mice is not known. Here we have generated mice expressing a mutant c-IAP1 that lacks E3 activity (c-IAP1(H582A)). These mice were phenotypically normal and did not have constitutive NF-kappaB activation in B cells or MEFs. siRNA-mediated knockdown of c-IAP2 showed that accumulated c-IAP2, resulting from lack of c-IAP1-dependent degradation, compensated for absent c-IAP1 E3 activity. Surprisingly, c-IAP1(H582A) T cells had a lower p100/p52 ratio than wild type T cells, and in the absence of costimulation proliferated to a degree intermediate between wild type and c-IAP2(H570A) T cells. Therefore, although c-IAP1 and c-IAP2 both can repress constitutive NF-kappaB activation, the relative importance of each varies according to cell type. |