Invariant chain, a chain of command

Invariant chain (li) is a type II integral membrane protein, which acts as a chaperone for MHC class II protein expression and facilitates antigen presentation. Recently, an additional role for li in the differentiation of immature to mature B cells has been described. These studies showed that Ii acts as a signaling molecule; its cytosolic domain induces B-cell maturation by activation of transcription mediated by the p65 member of the NF-kappaB family, a process that requires the B-cell-enriched coactivator, TAF(II)105. NF-kappaB activation is mediated by the cytosolic region of Ii, which is liberated from the membrane. The process of intramembrane cleavage followed by nuclear translocation and transcriptional activation is reminiscent of regulated intramembrane cleavage (RIP). In this Review we suggest that the behavior of li shows remarkable similarities to the function of proteins processed by RIP and propose that the roles of li as a chaperone and as a signaling molecule are intertwined.