Kaposi's sarcoma-associated herpesvirus inhibits interleukin-4-mediated STAT6 phosphorylation to regulate apoptosis and maintain latency.
Cytokine-mediated JAK/STAT signaling controls numerous important biologic responses like immune function, cellular growth, and differentiation. Inappropriate activation of this signaling pathway is associated with a range of malignancies. Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious viral agent associated with Kaposi's sarcoma and may also contribute to B-cell disorders, which include primary effusion lymphoma (PEL) and multicentric Castleman's disease. However, regulation of cytokine-mediated lymphocytic immune response by KSHV is not fully understood. In this report, we demonstrate that KSHV suppresses the interleukin-4 (IL-4)-stimulated immune response of B-lymphocyte activation and cell proliferation. Moreover, we show that the latency-associated nuclear antigen (LANA) encoded by KSHV is essential for viral blocking of IL-4-induced signaling. LANA reduces phosphorylation of the signal transducers and activators of transcription 6 (STAT6) on Y-641 and concomitantly its DNA binding ability. Importantly, knockdown of endogenous STAT6 dramatically increases the sensitivity of PEL cells to low-serum stress or chemical-mediated cellular apoptosis and reactivation of KSHV from latent replication. Thus, these findings suggest that the IL-4/STAT6 signaling network is precisely controlled by KSHV for survival, maintenance of latency, and suppression of the host cytokine immune response of the virus-infected cells.
Cai
Qiliang
Q
Department of Microbiology and the Tumor Virology Program, Abramson, Comprehensive Cancer Center, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
Verma
Subhash C
SC
Choi
Ji-Young
JY
Ma
Michelle
M
Robertson
Erle S
ES
D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006566:Herpesviridae Infections / Q000276:immunology / Q000821:virology; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D010766:Phosphorylation; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D017735:Virus Latency
D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4