Kaposi's sarcoma-associated herpesvirus latent protein LANA interacts with HIF-1 alpha to upregulate RTA expression during hypoxia: Latency control under low oxygen conditions.

Abstract

Hypoxia can induce lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) in primary effusion lymphoma (PEL) cells. However, the molecular mechanism of lytic reactivation of KSHV by hypoxia remains unclear. Here we show that the latency-associated nuclear antigen (LANA), which plays a crucial role in modulating viral and cellular gene expression, directly associated with a low oxygen responder, hypoxia-inducible factor-1 alpha (HIF-1 alpha). LANA enhanced not only the transcriptional activities of HIF-1 alpha but also its mRNA level. Coimmunoprecipitation and immunofluorescence studies documented a physical interaction between LANA and HIF-1 alpha in transiently transfected 293T cells as well as in PEL cell lines during hypoxia. Through sequence analysis, several putative hypoxia response elements (HRE-1 to -6) were identified in the essential lytic gene Rta promoter. Reporter assays showed that HRE-2 (-1130 to -1123) and HRE-5 and HRE-6 (+234 to +241 and +812 to +820, respectively, within the intron sequence) were necessary and sufficient for the LANA-mediated HIF-1 alpha response. Electrophoretic mobility shift assays showed HIF-1 alpha-dependent binding of a LANA protein complex specifically to the HRE-2, -5, and -6 motifs within the promoter regulatory sequences. This study demonstrates that hypoxia-induced KSHV lytic replication is mediated at least in part through cooperation of HIF-1 alpha with LANA bound to the HRE motifs of the Rta promoter.

• Authors: Qiliang Cai, Ke Lan, Subhash C Verma, Huaxin Si, Doug Lin, Erle S Robertson
• Journal: Journal of virology (J Virol) Vol. 80 Issue 16 Pg. 7965-75 (Aug 2006) ISSN: 0022-538X [Print] United States
• PMID: 16873253 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Viral
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Immediate-Early Proteins
• Nuclear Proteins
• RNA, Messenger
• Rta protein, Human herpesvirus 8
• Trans-Activators
• Viral Proteins
• latency-associated nuclear antigen
• Oxygen

Topics

• Anaerobiosis (genetics)
• Antigens, Viral (metabolism)
• Gene Expression Regulation, Viral
• Herpesvirus 8, Human (genetics, physiology)
• Humans
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Immediate-Early Proteins (genetics)
• Nuclear Proteins (metabolism)
• Oxygen (metabolism)
• Promoter Regions, Genetic (genetics)
• RNA, Messenger (metabolism)
• Response Elements (genetics)
• Trans-Activators (genetics)
• Transcription, Genetic
• Viral Proteins (genetics)
• Virus Replication (genetics)