Kaposi's Sarcoma Herpesvirus Viral FLICE Inhibitory Protein Modulates A20 Deubiquitinase Activity

Overview

Journal Access Microbiol

Specialty Microbiology

Date 2024 Jun 13

PMID 38868372

Authors

Kevin Herold

Ayana Ruffin

Jennifer C Chmura

Anna J Dellomo

Elana S Ehrlich

Affiliations

Soon will be listed here.

Abstract

KSHV viral FLICE inhibitory protein (vFLIP) is a potent activator of NF-κB signalling and an inhibitor of apoptosis and autophagy. Inhibition of vFLIP function and NF-κB signalling promotes lytic reactivation. Here we provide evidence for a novel function of vFLIP through inhibition of the deubiquitinating (DUB) activity of the negative regulator, A20. We demonstrate direct interaction of vFLIP with Itch and A20 and provide evidence for subsequent loss of A20 DUB activity. Our results provide further insight into the function of vFLIP in the regulation of NF-κB signalling.

References

Polizzotto M, Uldrick T, Hu D, Yarchoan R . Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome. Front Microbiol. 2012; 3:73. PMC: 3291870. DOI: 10.3389/fmicb.2012.00073. View

Chmura J, Herold K, Ruffin A, Atuobi T, Fabiyi Y, Mitchell A . The Itch ubiquitin ligase is required for KSHV RTA induced vFLIP degradation. Virology. 2016; 501:119-126. PMC: 5271570. DOI: 10.1016/j.virol.2016.11.016. View

Lee H, Li F, Choi U, Yu H, Aldrovandi G, Feng P . Deregulation of HDAC5 by Viral Interferon Regulatory Factor 3 Plays an Essential Role in Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphangiogenesis. mBio. 2018; 9(1). PMC: 5770555. DOI: 10.1128/mBio.02217-17. View

Hunte R, Alonso P, Thomas R, Bazile C, Ramos J, van der Weyden L . CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-κB activation. PLoS Pathog. 2018; 14(4):e1006968. PMC: 5919438. DOI: 10.1371/journal.ppat.1006968. View

Ehrlich E, Chmura J, Smith J, Kalu N, Hayward G . KSHV RTA abolishes NFκB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome. PLoS One. 2014; 9(3):e91359. PMC: 3948842. DOI: 10.1371/journal.pone.0091359. View

Lee E, Boone D, Chai S, Libby S, Chien M, Lodolce J . Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science. 2000; 289(5488):2350-4. PMC: 3582399. DOI: 10.1126/science.289.5488.2350. View

Brown H, Song M, Deng H, Wu T, Cheng G, Sun R . NF-kappaB inhibits gammaherpesvirus lytic replication. J Virol. 2003; 77(15):8532-40. PMC: 165238. DOI: 10.1128/jvi.77.15.8532-8540.2003. View

Ma A, Malynn B . A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol. 2012; 12(11):774-85. PMC: 3582397. DOI: 10.1038/nri3313. View

Dissinger N, Damania B . Recent advances in understanding Kaposi's sarcoma-associated herpesvirus. F1000Res. 2016; 5. PMC: 4847565. DOI: 10.12688/f1000research.7612.1. View

10.

Tolani B, Matta H, Gopalakrishnan R, Punj V, Chaudhary P . NEMO is essential for Kaposi's sarcoma-associated herpesvirus-encoded vFLIP K13-induced gene expression and protection against death receptor-induced cell death, and its N-terminal 251 residues are sufficient for this process. J Virol. 2014; 88(11):6345-54. PMC: 4093867. DOI: 10.1128/JVI.00028-14. View

11.

Shembade N, Pujari R, Harhaj N, Abbott D, Harhaj E . The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1. Nat Immunol. 2011; 12(9):834-43. PMC: 3205447. DOI: 10.1038/ni.2066. View

12.

Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F . Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature. 1997; 386(6624):517-21. DOI: 10.1038/386517a0. View

13.

Matta H, Mazzacurati L, Schamus S, Yang T, Sun Q, Chaudhary P . Kaposi's sarcoma-associated herpesvirus (KSHV) oncoprotein K13 bypasses TRAFs and directly interacts with the IkappaB kinase complex to selectively activate NF-kappaB without JNK activation. J Biol Chem. 2007; 282(34):24858-65. DOI: 10.1074/jbc.M700118200. View

14.

Ding X, Xu J, Wang C, Feng Q, Wang Q, Yang Y . Suppression of the SAP18/HDAC1 complex by targeting TRIM56 and Nanog is essential for oncogenic viral FLICE-inhibitory protein-induced acetylation of p65/RelA, NF-κB activation, and promotion of cell invasion and angiogenesis. Cell Death Differ. 2019; 26(10):1970-1986. PMC: 6748093. DOI: 10.1038/s41418-018-0268-3. View

15.

Nakayama R, Ueno Y, Ueda K, Honda T . Latent infection with Kaposi's sarcoma-associated herpesvirus enhances retrotransposition of long interspersed element-1. Oncogene. 2019; 38(22):4340-4351. DOI: 10.1038/s41388-019-0726-5. View

16.

Yang Z, Honda T, Ueda K . vFLIP upregulates IKKε, leading to spindle morphology formation through RelA activation. Virology. 2018; 522:106-121. DOI: 10.1016/j.virol.2018.07.007. View

17.

Sakakibara S, Espigol-Frigole G, Gasperini P, Uldrick T, Yarchoan R, Tosato G . A20/TNFAIP3 inhibits NF-κB activation induced by the Kaposi's sarcoma-associated herpesvirus vFLIP oncoprotein. Oncogene. 2012; 32(10):1223-32. PMC: 3594048. DOI: 10.1038/onc.2012.145. View

18.

Cesarman E, Damania B, Krown S, Martin J, Bower M, Whitby D . Kaposi sarcoma. Nat Rev Dis Primers. 2019; 5(1):9. PMC: 6685213. DOI: 10.1038/s41572-019-0060-9. View

19.

Bravo Cruz A, Damania B . Models of Oncoproteins Encoded by Kaposi's Sarcoma-Associated Herpesvirus. J Virol. 2019; 93(11). PMC: 6532075. DOI: 10.1128/JVI.01053-18. View

20.

Chaudhary P, Jasmin A, Eby M, Hood L . Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene. 1999; 18(42):5738-46. DOI: 10.1038/sj.onc.1202976. View