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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Motifs
-
Antigens, Viral / genetics
-
Antigens, Viral / metabolism*
-
Cell Line, Tumor
-
HEK293 Cells
-
Herpesvirus 8, Human / physiology*
-
Humans
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism*
-
Plasmids / genetics
-
Plasmids / metabolism
-
Repressor Proteins / genetics
-
Repressor Proteins / metabolism
-
Sin3 Histone Deacetylase and Corepressor Complex
-
Small Ubiquitin-Related Modifier Proteins / genetics
-
Small Ubiquitin-Related Modifier Proteins / metabolism*
-
Sumoylation / genetics
-
Tripartite Motif-Containing Protein 28
-
Viral Proteins / genetics
-
Viral Proteins / metabolism*
-
Virus Latency / physiology*
-
Xeroderma Pigmentosum / genetics
-
Xeroderma Pigmentosum / metabolism
-
Xeroderma Pigmentosum / pathology
Substances
-
Antigens, Viral
-
Nuclear Proteins
-
Repressor Proteins
-
SIN3A transcription factor
-
SUMO2 protein, human
-
Small Ubiquitin-Related Modifier Proteins
-
Viral Proteins
-
latency-associated nuclear antigen
-
TRIM28 protein, human
-
Tripartite Motif-Containing Protein 28
-
Sin3 Histone Deacetylase and Corepressor Complex