Identification of the Merkel Cell Polyomavirus Large Tumor Antigen Ubiquitin Conjugation Residue

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jul 20

PMID 34281220

Citations 6

Authors

Luz E Ortiz

Alexander M Pham

Hyun Jin Kwun

Affiliations

Soon will be listed here.

Abstract

Merkel cell polyomavirus (MCPyV) large tumor (LT) antigen is a DNA binding protein essential for viral gene transcription and genome replication. MCPyV LT interacts with multiple E3 ligases in a phosphorylation-dependent manner, limiting its own viral replication by enhancing LT protein degradation, which is a unique mechanism for MCPyV latency. Thus, identifying LT ubiquitination sites is an important step toward understanding the biological role of these virus-host interactions that can potentially result in viral oncogenesis. The ubiquitin (Ub) attachment sites in LT were predicted by using Rapid UBIquitination (RUBI), a sequence-based ubiquitination web server. Using an immunoprecipitation approach, the lysine (Lys, K) 585 residue in LT is identified as the ubiquitin conjugation site. Lysine 585 is deleted from tumor-derived truncated LTs (tLTs), resulting in stable expression of tLTs present in cancers. Substitution of lysine 585 to arginine (Arg, R) increased LT protein stability, but impaired MCPyV origin replication, due to a loss of ATP hydrolysis activity. These findings uncover a never-before-identified ubiquitination site of LT and its importance not only in the regulation of protein turnover, but also in MCPyV genome replication.

Citing Articles

The Role of the Large T Antigen in the Molecular Pathogenesis of Merkel Cell Carcinoma.

Myrda J, Bremm F, Schaft N, Dorrie J Genes (Basel). 2024; 15(9).

PMID: 39336718 PMC: 11431464. DOI: 10.3390/genes15091127.

Merkel cell carcinoma: updates in tumor biology, emerging therapies, and preclinical models.

Pedersen E, Verhaegen M, Joseph M, Harms K, Harms P Front Oncol. 2024; 14:1413793.

PMID: 39136002 PMC: 11317257. DOI: 10.3389/fonc.2024.1413793.

Casein kinase 1α mediates phosphorylation of the Merkel cell polyomavirus large T antigen for β-TrCP destruction complex interaction and subsequent degradation.

Pham A, Kwun H mBio. 2024; 15(8):e0111724.

PMID: 38940554 PMC: 11323502. DOI: 10.1128/mbio.01117-24.

A functional and structural comparative analysis of large tumor antigens reveals evolution of different importin α-dependent nuclear localization signals.

Cross E, Akbari N, Ghassabian H, Hoad M, Pavan S, Ariawan D Protein Sci. 2023; 33(2):e4876.

PMID: 38108201 PMC: 10807245. DOI: 10.1002/pro.4876.

Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain.

Pham A, Ortiz L, Lukacher A, Kwun H Cells. 2023; 12(3).

PMID: 36766726 PMC: 9913222. DOI: 10.3390/cells12030380.

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