NEDDylation is essential for Kaposi's sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target

PLoS Pathogens
David J HughesAdrian Whitehouse

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-κB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment...Continue Reading

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Citations

Feb 26, 2016·Frontiers in Microbiology·Suhani Thakker, Subhash C Verma
May 18, 2016·The Journal of General Virology·Sophie SchumannAdrian Whitehouse
Dec 14, 2016·Trends in Microbiology·Barbara AdlerHeiko Adler
Feb 21, 2018·The Journal of Biological Chemistry·Gabrielė StakaitytėAdrian Whitehouse
Nov 3, 2017·Journal of Virology·Gabrielė StakaitytėAdrian Whitehouse
Aug 12, 2016·Journal of Virology·Jennifer J WoodDavid J Hughes
Nov 28, 2017·Cellular & Molecular Immunology·Kun Han, Jiyan Zhang
Sep 24, 2016·Current Opinion in HIV and AIDS·Priscila H GoncalvesRobert Yarchoan
Aug 5, 2020·Immunity, Inflammation and Disease·Yun Lu, Xuguang Yang
Apr 17, 2019·International Journal of Molecular Sciences·Tanja BeckerMirko Trilling
Oct 6, 2020·The Journal of General Virology·Yucen LiXin Ye
Oct 8, 2020·The FEBS Journal·Tao Zou, Jiyan Zhang
Jan 13, 2021·Microbiology and Immunology·David Virya ChenToru Okamoto
Jun 30, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Huiqing XiuGensheng Zhang
Nov 9, 2021·The Journal of General Virology·Wen-Ying LongYao Wu

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Methods Mentioned

BETA
immunoprecipitation
transfection
transfections
ChIP
nuclear translocation
co-immunoprecipitation
Assay
PCR

Software Mentioned

ZEN
ImageJ

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