title: Kaposi's sarcoma-associated herpesvirus kaposin B induces unique monophosphorylation of STAT3 at serine 727 and MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and the inflammation-driven neoplasm Kaposi's sarcoma (KS). A triad of processes, including abnormal proliferation of endothelial cells, aberrant angiogenesis, and chronic inflammation, characterize KS lesions. STAT3 is a key transcription factor governing these processes, and deregulation of STAT3 activity is linked to a wide range of cancers, including PEL and KS. Using primary human endothelial cells (ECs), I demonstrate that KSHV infection modulated STAT3 activation in two ways: (i) KSHV induced uncoupling of canonical tyrosine (Y) and serine (S) phosphorylation events while (ii) concomitantly inducing the phosphorylation and inactivation of TRIM28 (also known as KAP-1 or TIF-1β), a newly identified negative regulator of STAT3 activity. KSHV infection of primary ECs induced chronic STAT3 activation characterized by a shift from the canonical dual P-STAT3 Y705 S727 form to a mono P-STAT3 S727 form. Expression of the latent protein kaposin B promoted the unique phosphorylation of STAT3 at S727, in the absence of Y705, activated the host kinase mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), and stimulated increased expression of STAT3-dependent genes, including CCL5, in ECs. TRIM28-mediated repression of STAT3 is relieved by phosphorylation of S473, and in vitro kinase assays identified TRIM28 S473 as a bona fide target of MK2. Together, these data suggest that kaposin B significantly contributes to the chronic inflammatory environment that is a hallmark of KS by unique activation of the proto-oncogene STAT3, coupled with MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28.
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA. kingch@upstate.edu
authors.forename: Christine A
authors.initials: CA
authors.lastname: King
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000821:virology; D019288:Herpesvirus 8, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28; D014764:Viral Proteins / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000076183:Tripartite Motif-Containing Protein 28; D014764:Viral Proteins; D000099190:MAP-Kinase-Activated Kinase 2; C000715470:MAS1 protein, human; C494086:STAT3 protein, human; C120136:kaposin B protein, Human herpesvirus 8; C101116:TRIM28 protein, human