The c-Cbl proto-oncoprotein downregulates EBV LMP2A signaling.
Latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) plays a key role in regulating viral latency and EBV pathogenesis by functionally mimicking signals induced by the B-cell receptor (BCR) altering normal B cell development. As c-Cbl ubiquitin ligase (E3) is a critical negative regulator in the BCR signal pathway, the role of c-Cbl in the function and formation of the LMP2A signalosome was examined. c-Cbl promoted LMP2A degradation through ubiquitination, specifically degraded the Syk protein tyrosine kinase in the presence of LMP2A, and inhibited LMP2A induction of the EBV lytic cycle. Our earlier studies indicated that LMP2A-dependent Lyn degradation was mediated by Nedd4-family E3s in LMP2A expressing cells. Combine with these new findings, we propose a model in which c-Cbl and Nedd4-family E3s cooperate to degrade target proteins at discrete steps in the function of the LMP2A signalosome.
Ikeda
Masato
M
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Longnecker
Richard
R
D000818:Animals; D016466:CHO Cells; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport; D020031:Epstein-Barr Virus Infections / Q000378:metabolism* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D056827:Endosomal Sorting Complexes Required for Transport; D047908:Intracellular Signaling Peptides and Proteins; D014763:Viral Matrix Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases