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Exploiting Ubiquitin Ligases for Induced Target Degradation as an Antiviral Strategy

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Antiviral Drug Discovery and Development

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1322))

Abstract

Posttranslational modifications of targeted substrates alter their cellular fate. Ubiquitin is a highly conserved and ubiquitous covalent modifier protein that tags substrates with a single molecule or with a polyubiquitin chain. Monoubiquitination affects trafficking and signaling patterns of modified proteins. In contrast, polyubiquitination, particularly K48-linked polyubiquitination, targets the protein for degradation by the Ubiquitin-Proteasome System (UPS) resulting in a committed fate through irreversible inactivation of substrate. Given the diversity of cellular functions impacted by ubiquitination, it is no surprise that the wily pathogenic viruses have co-opted the UPS in myriad ways to ensure their survival. In this review, I describe viral exploitation of nondegradative ubiquitin signaling pathways to effect entry, replication, and egress. Additionally, viruses also harness the UPS to degrade antiviral cellular host factors. Finally, I describe how we can exploit the same proteolytic machinery to enable PROTACs (Proteolysis-Targeting Chimeras) to degrade essential viral proteins. Successful implementation of this modality will add to the arsenal of emerging antiviral therapies.

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Abbreviations

AdV:

Adenovirus

ARIH2:

Protein Ariadne-2 homolog

ART:

Arrestin-related trafficking proteins

bTRCP:

Beta-transducin repeat containing

CARDs:

Caspase activation and recruitment domains

cGAMP:

Cyclic guanosine monophosphate–adenosine monophosphate

cGAS:

Cyclic GMP-AMP synthase

CRBN:

Cereblon

CRL:

Cullin-RING ligase

DDB1:

DNA damage-binding protein 1

DUBs:

Deubiquitinases

EBOV:

Ebola virus

EBV:

Epstein barr virus

ESCRT:

Endosomal sorting complex required for transport

HBV:

Hepatitis B virus

HCMV:

Human cytomegalovirus

HDAC6:

Histone deacetylase 6

HECT:

Homologous to E6-AP Carboxyl Terminus

HEXIM1:

Hexamethylene bisacetamide inducible 1

HIV-1:

Human immunodeficiency virus type 1

HPV:

Human papillomavirus

HRSV:

Human respiratory syncytial virus

HSV-1:

Herpes simplex virus 1

HTLV-1:

Human T lymphotropic virus type 1

IAV:

Influenza A virus

IFN:

Interferon

IMiD:

Immunomodulatory

IRF3:

IFN-regulatory factor 3

ISG15:

Interferon stimulated gene 15

KSHV:

Kaposi’s Sarcoma herpes virus

LUBAC:

Linear Ub chain assembly complex

MAVS:

Mitochondrial antiviral signaling protein

MHC:

Major histocompatibility complex

NEDD4:

Neural precursor cell expressed developmentally down-regulated

PAMPs:

Pathogen-associated molecular patterns

PLPro:

Papain-like protease

PML-NB:

Promyelocytic Leukemia Protein-Nuclear Body

PPIs:

Protein:protein interaction interface

PROTACs:

Proteolysis targeting chimeras

PRR:

Pattern recognition receptors

RBR:

RING-between-ring

RIG-1:

Retinoic acid-inducible gene 1

RING:

Really interesting new gene

RNP:

Ribonucleoprotein particle

RSV:

Rous sarcoma virus

SARS-CoV:

Severe acute respiratory syndrome coronavirus

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus 2

SM:

Small molecule

STAT:

Signal transducer and activator of transcription

STING:

Stimulator of interferon genes

TAK1:

TGFb-activated kinase 1

TBK1:

TANK-binding kinase-1

TNF:

Tumor necrosis factor

TRAF:

TNF receptor-associated factor

TRIM:

Tripartite motif

Ub:

Ubiquitin

UPS:

Ubiquitin-proteasome system

VHL:

Von Hippel Lindau

VIF:

Viral infectivity factor

ZIKV:

Zika virus

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Acknowledgments

I would like to thank my colleagues Dane Mohl and Ryan Wurtz for comments and help with the Figs. I apologize to TPD researchers whose work could not be cited due to space limitations.

Declaration of Interests

I am an employee and shareholder of AMGEN.

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  1. AMGEN Research, One Amgen Center Drive, Thousand Oaks, CA, USA

    Rati Verma

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  1. Rati Verma
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Correspondence to Rati Verma .

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  1. School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China

    Xinyong Liu

  2. School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China

    Peng Zhan

  3. – Centro de Biología Molecular “Severo Ochoa” – Spanish National Research Council (CSIC), Madrid, Madrid, Spain

    Luis Menéndez-Arias

  4. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark

    Vasanthanathan Poongavanam

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Verma, R. (2021). Exploiting Ubiquitin Ligases for Induced Target Degradation as an Antiviral Strategy. In: Liu, X., Zhan, P., Menéndez-Arias, L., Poongavanam, V. (eds) Antiviral Drug Discovery and Development. Advances in Experimental Medicine and Biology, vol 1322. Springer, Singapore. https://doi.org/10.1007/978-981-16-0267-2_13

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