Abstract
Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with a high metastatic potential. The majority of MCC cases are caused by the Merkel cell polyomavirus (MCPyV), through expression of the virus-encoded tumour antigens. Whilst mechanisms attributing tumour antigen expression to transformation are being uncovered, little is known of the mechanisms by which MCPyV persists in the host. We previously identified the MCPyV small T antigen (tAg) as a novel inhibitor of nuclear factor kappa B (NF-kB) signalling and a modulator of the host anti-viral response. Here we demonstrate that regulation of NF-kB activation involves a previously undocumented interaction between tAg and regulatory sub-unit 1 of protein phosphatase 4 (PP4R1). Formation of a complex with PP4R1 and PP4c is required to bridge MCPyV tAg to the NEMO adaptor protein, allowing deactivation of the NF-kB pathway. Mutations in MCPyV tAg that fail to interact with components of this complex, or siRNA depletion of PP4R1, prevents tAg-mediated inhibition of NF-kB and pro-inflammatory cytokine production. Comparison of tAg binding partners from other human polyomavirus demonstrates that interactions with NEMO and PP4R1 are unique to MCPyV. Collectively, these data identify PP4R1 as a novel target for virus subversion of the host anti-viral response.
Highlights
Merkel Cell Carcinoma (MCC) is a rare and highly malignant neuroendocrine carcinoma of the skin with a high level of metastasis and poor five-year survival rate [1, 2]
Mutations in the ubiquitin-binding in ABIN and NEMO (UBAN) domain of NFκB essential modulator (NEMO) prevent the interaction with Merkel cell polyomavirus (MCPyV) T antigen (tAg) in cells We previously demonstrated that tAg interacts with NEMO in cells [10]
Whilst these internal deletions expressed to wild-type levels, only the coiledcoil domain deletion bound to tAg at similar levels to wild type NEMO, whereas the leucine zipper deletion mutant abrogated the interaction with tAg (Figure 1C)
Summary
Merkel Cell Carcinoma (MCC) is a rare and highly malignant neuroendocrine carcinoma of the skin with a high level of metastasis and poor five-year survival rate [1, 2]. In keeping with other polyomaviruses, MCPyV expresses early proteins including the large (TAg) and small (tAg) tumour antigens, and a number of splice variants thereof [4]. These function as regulatory proteins and are essential for virus replication and pathogenesis. MCPyV T-antigens are essential for MCC cell survival and proliferation, and depletion of either protein using siRNA leads to cell cycle arrest and apoptosis [4] In agreement with these observations, mice genetically engineered to express MCPyV T antigens in the stratified epithelium display signs of neoplastic progression including unscheduled DNA synthesis, increased cellular proliferation and evidence of DNA damage.
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