CD74 is a member of the regulated intramembrane proteolysis-processed protein family.
Quite a few regulatory proteins, including transcription factors, are normally maintained in a dormant state to be activated after internal or environmental cues. Recently, a novel strategy, requiring proteolytic cleavage, was described for the mobilization of dormant transcription factors. These transcription factors are initially synthesized in an inactive form, whereas "nesting" in integral membrane precursor proteins. After a cleavage event, these new active factors are released from the membrane and can migrate into the nucleus to drive regulated gene transcription. This mechanism, regulated intramembrane proteolysis (RIP), controls diverse biological processes in prokaryotes and eukaryotes in response to a variety of signals. The MHC class II chaperone, CD74 (invariant chain, Ii), was previously shown to function as a signaling molecule in several pathways. Recently, we demonstrated that after intramembranal cleavage, the CD74 cytosolic fragment (CD74-ICD) is released and induces activation of transcription mediated by the NF-kappaB p65/RelA homodimer and the B-cell-enriched coactivator, TAF(II)105. Here, we add CD74 to the growing family of RIP-processed proteins. Our studies show that CD74 ectodomain must be processed in the endocytic compartments to allow its intramembrane cleavage that liberates CD74 intracellular domain (CD74-ICD). We demonstrate that CD74-ICD translocates to the nucleus and induces the activation of the p65 member of NF-kappaB in this compartment.
Becker-Herman
Shirly
S
Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel.
Arie
Galit
G
Medvedovsky
Helena
H
Kerem
Anat
A
Shachar
Idit
I
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D013154:Spleen; D051996:Transcription Factor RelA; D014157:Transcription Factors; D015533:Transcriptional Activation; D014162:Transfection
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014157:Transcription Factors; C045084:invariant chain