CD74 induces TAp63 expression leading to B-cell survival

Abstract

Most mature follicular B cells circulate within the periphery in a quiescent state, without actively contributing to an acute immune response. Lasting B-cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. We recently demonstrated that cell surface CD74 controls mature B-cell survival. Stimulation of cell surface CD74 leads to NF-B activation, which enables entry of the stimulated B cells into the S phase, induction of DNA synthesis, and cell division, and augments the expression of survival genes. In the present study, we investigated CD74 target genes to determine the identities of the molecules whose expression is modulated by CD74, thereby regulating B-cell survival. We report that CD74 activates the p65 member of the NF-B family, which in turn up-regulates the expression of p53-related TAp63 proteins. IntroductionIn healthy individuals, the pool of peripheral lymphocytes is constant in size. The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, survival, and proliferation. Survival factors have been shown to play a critical role in maintaining lymphocyte homeostasis.Recently, we demonstrated that CD74 (invariant chain, Ii) controls mature B-cell survival. CD74 is a nonpolymorphic type II integral membrane protein, containing a short N-terminal cytoplasmic tail of 28 amino acids (aa's), followed by a single 24-aa transmembrane region, and an approximately 150-aa lumenal domain. The CD74 chain was originally thought to function mainly as an MHC class II chaperone, promoting the exit of MHC class II molecules from the endoplasmic reticulum (ER), directing them to endocytic compartments, preventing peptide binding within the ER, and contributing to peptide editing in the MHC class II compartment. 1 However, CD74 was recently found to play an additional role as an accessory signaling molecule. A small proportion of CD74 is modified by the addition of chondroitin sulfate (CD74-CS), and this form of CD74 is expressed on the surface of antigen-presenting cells together with CD44. 2,3 In macrophages, CD74 was recently reported to demonstrate high-affinity binding to the proinflammatory cytokine, macrophage migration-inhibitory factor (MIF). MIF binds to the extracellular domain of CD74, and this interaction is required for MIF-mediated cell proliferation. 4 In a previous series of studies, we showed that CD74 is directly involved in shaping the B-cell repertoire 5 through a pathway leading to the activation of transcription mediated by the NF-B p65/RelA homodimer and its coactivator, TAFII105. 6 NF-B activation is mediated by the cytosolic region of CD74 (CD74-ICD), which is liberated from the membrane. 7 We demonstrated that following the removal of the CD74 lumenal domain, an intramembranal cleavage event at amino acid 42 occurs, resulting in the release of the CD74 cytosolic fragment (CD74-ICD; aa's 1-42). CD74-ICD, which has no NLS motif, then translocates to the nucleus and activates NF-B. 8 Thus, fol...

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