Merkel cell polyomavirus small tumor antigen contributes to immune evasion by interfering with type I interferon signaling
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Merkel cell polyomavirus small tumor antigen contributes to immune evasion by interfering with type I interferon signaling. / Ohnezeit, Denise; Huang, Jiabin; Westerkamp, Ute; Brinschwitz, Veronika; Schmidt, Claudia; Günther, Thomas; Czech-Sioli, Manja; Weißelberg, Samira; Schlemeyer, Tabea; Nakel, Jacqueline; Mai, Julia; Schreiner, Sabrina; Schneider, Carola; Friedel, Caroline C; Schwanke, Hella; Brinkmann, Melanie M; Grundhoff, Adam; Fischer, Nicole.
in: PLOS PATHOG, Jahrgang 20, Nr. 8, e1012426, 08.2024.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Merkel cell polyomavirus small tumor antigen contributes to immune evasion by interfering with type I interferon signaling
AU - Ohnezeit, Denise
AU - Huang, Jiabin
AU - Westerkamp, Ute
AU - Brinschwitz, Veronika
AU - Schmidt, Claudia
AU - Günther, Thomas
AU - Czech-Sioli, Manja
AU - Weißelberg, Samira
AU - Schlemeyer, Tabea
AU - Nakel, Jacqueline
AU - Mai, Julia
AU - Schreiner, Sabrina
AU - Schneider, Carola
AU - Friedel, Caroline C
AU - Schwanke, Hella
AU - Brinkmann, Melanie M
AU - Grundhoff, Adam
AU - Fischer, Nicole
N1 - Copyright: © 2024 Ohnezeit et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2024/8
Y1 - 2024/8
N2 - Merkel cell polyomavirus (MCPyV) is the causative agent of the majority of Merkel cell carcinomas (MCC). The virus has limited coding capacity, with its early viral proteins, large T (LT) and small T (sT), being multifunctional and contributing to infection and transformation. A fundamental difference in early viral gene expression between infection and MCPyV-driven tumorigenesis is the expression of a truncated LT (LTtr) in the tumor. In contrast, sT is expressed in both conditions and contributes significantly to oncogenesis. Here, we identified novel functions of early viral proteins by performing genome-wide transcriptome and chromatin studies in primary human fibroblasts. Due to current limitations in infection and tumorigenesis models, we mimic these conditions by ectopically expressing sT, LT or LTtr, individually or in combination, at different time points. In addition to its known function in cell cycle and inflammation modulation, we reveal a fundamentally new function of sT. We show that sT regulates the type I interferon (IFN) response downstream of the type I interferon receptor (IFNAR) by interfering with the interferon-stimulated gene factor 3 (ISGF3)-induced interferon-stimulated gene (ISG) response. Expression of sT leads to a reduction in the expression of interferon regulatory factor 9 (IRF9) which is a central component of the ISGF3 complex. We further show that this function of sT is conserved in BKPyV. We provide a first mechanistic understanding of which early viral proteins trigger and control the type I IFN response, which may influence MCPyV infection, persistence and, during MCC progression, regulation of the tumor microenvironment.
AB - Merkel cell polyomavirus (MCPyV) is the causative agent of the majority of Merkel cell carcinomas (MCC). The virus has limited coding capacity, with its early viral proteins, large T (LT) and small T (sT), being multifunctional and contributing to infection and transformation. A fundamental difference in early viral gene expression between infection and MCPyV-driven tumorigenesis is the expression of a truncated LT (LTtr) in the tumor. In contrast, sT is expressed in both conditions and contributes significantly to oncogenesis. Here, we identified novel functions of early viral proteins by performing genome-wide transcriptome and chromatin studies in primary human fibroblasts. Due to current limitations in infection and tumorigenesis models, we mimic these conditions by ectopically expressing sT, LT or LTtr, individually or in combination, at different time points. In addition to its known function in cell cycle and inflammation modulation, we reveal a fundamentally new function of sT. We show that sT regulates the type I interferon (IFN) response downstream of the type I interferon receptor (IFNAR) by interfering with the interferon-stimulated gene factor 3 (ISGF3)-induced interferon-stimulated gene (ISG) response. Expression of sT leads to a reduction in the expression of interferon regulatory factor 9 (IRF9) which is a central component of the ISGF3 complex. We further show that this function of sT is conserved in BKPyV. We provide a first mechanistic understanding of which early viral proteins trigger and control the type I IFN response, which may influence MCPyV infection, persistence and, during MCC progression, regulation of the tumor microenvironment.
U2 - 10.1371/journal.ppat.1012426
DO - 10.1371/journal.ppat.1012426
M3 - SCORING: Journal article
C2 - 39110744
VL - 20
JO - PLOS PATHOG
JF - PLOS PATHOG
SN - 1553-7366
IS - 8
M1 - e1012426
ER -