MLL1 is regulated by KSHV LANA and is important for virus latency

Tan, Min; Li, Shijun; Juillard, Franceline; Chitas, Rute; Custódio, Tânia F.; Xue, Han; Szymula, Agnieszka; Sun, Qiming; Liu, Bing; Álvarez, Ángel L.; Chen, She; Huang, Jing; Simas, J. Pedro; McVey, Colin E.; Kaye, Kenneth M.

doi:10.1093/nar/gkab1094

MLL1 is regulated by KSHV LANA and is important for virus latency

Journal Article · Sun Nov 28 23:00:00 EST 2021 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkab1094· OSTI ID:1833476

Tan, Min ^[1]; Li, Shijun ^[1]; Juillard, Franceline ^[1]; Chitas, Rute ^[2]; Custódio, Tânia F. ^[2]; Xue, Han ^[3]; Szymula, Agnieszka ^[1]; Sun, Qiming ^[4]; Liu, Bing ^[1]; ^[1]; ^[5]; ^[6]; Simas, J. Pedro ^[7]; McVey, Colin E. ^[2]; ^[1]

Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras 2780-157, Portugal
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China
Departments of Biochemistry and Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Proteomics Center, National Institute of Biological Sciences, Beijing 102206, China
State Key Laboratory of Oncogenes and Related Genes, Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine 200125 Shanghai, China
Instituto de Medicina Molecular, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal, Católica Biomedical Research, Católica Medical School, Universidade Católica Portuguesa, Palma de Cima, 1649-023 Lisboa, Portugal

Abstract

Mixed lineage leukemia 1 (MLL1) is a histone methyltransferase. Kaposi's sarcoma-associated herpesvirus (KSHV) is a leading cause of malignancy in AIDS. KSHV latently infects tumor cells and its genome is decorated with epigenetic marks. Here, we show that KSHV latency-associated nuclear antigen (LANA) recruits MLL1 to viral DNA where it establishes H3K4me3 modifications at the extensive KSHV terminal repeat elements during primary infection. LANA interacts with MLL1 complex members, including WDR5, integrates into the MLL1 complex, and regulates MLL1 activity. We describe the 1.5-Å crystal structure of N-terminal LANA peptide complexed with MLL1 complex member WDR5, which reveals a potential regulatory mechanism. Disruption of MLL1 expression rendered KSHV latency establishment highly deficient. This deficiency was rescued by MLL1 but not by catalytically inactive MLL1. Therefore, MLL1 is LANA regulable and exerts a central role in virus infection. These results suggest broad potential for MLL1 regulation, including by non-host factors.

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Sponsoring Organization:: USDOE Office of Nuclear Energy (NE), Nuclear Fuel Cycle and Supply Chain

OSTI ID:: 1833476

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 22 Vol. 49; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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