title: A unique SUMO-2-interacting motif within LANA is essential for KSHV latency.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) stabilizes hypoxia-inducible factor α (HIF-1α) during latent infection, and HIF-1α reactivates lytic replication under hypoxic stress. However, the mechanism utilized by KSHV to block lytic reactivation with the accumulation of HIF-1α in latency remains unclear. Here, we report that LANA encoded by KSHV contains a unique SUMO-interacting motif (LANA(SIM)) which is specific for interaction with SUMO-2 and facilitates LANA SUMOylation at lysine 1140. Proteomic and co-immunoprecipitation analysis further reveal that the SUMO-2 modified transcription repressor KAP1 is a critical factor recruited by LANA(SIM). Deletion of LANA(SIM) led to functional loss of both LANA-mediated viral episome maintenance and lytic gene silencing. Moreover, hypoxia reduced KAP1 SUMOylation and resulted in dissociation of both KAP1 and Sin3A repressors from LANA(SIM)-associated complex. Therefore, the LANA(SIM) motif plays an essential role in KSHV latency and is a potential drug target against KSHV-associated cancers.
authors.affiliation: MOE & MOH Key Laboratory of Medical Molecular Virology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China ; Department of Microbiology and Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America.
authors.forename: Qiliang
authors.initials: Q
authors.lastname: Cai
authors.forename: Shen
authors.initials: S
authors.lastname: Cai
authors.forename: Caixia
authors.initials: C
authors.lastname: Zhu
authors.forename: Suhbash C
authors.initials: SC
authors.lastname: Verma
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D020816:Amino Acid Motifs; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000235:genetics; D000076183:Tripartite Motif-Containing Protein 28; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency / Q000502:physiology*; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000956:Antigens, Viral; D009687:Nuclear Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014764:Viral Proteins; C109540:latency-associated nuclear antigen; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D056264:Sin3 Histone Deacetylase and Corepressor Complex