{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:53:55Z","timestamp":1791554035792,"version":"4.3.4"},"reference-count":49,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Pennsylvania Department of Health","award":["SAP# 4100083097"],"award-info":[{"award-number":["SAP# 4100083097"]}],"id":[{"id":"https:\/\/ror.org\/00ra1fg11","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2024,8,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Merkel cell polyomavirus (MCPyV) is a double-stranded tumor virus that is the main causative agent of Merkel cell carcinoma (MCC). The MCPyV large T antigen (LT), an essential viral DNA replication protein, maintains viral persistence by interacting with host Skp1-Cullin 1-F-box (SCF) E3 ubiquitin ligase complexes, which subsequently induces LT\u2019s proteasomal degradation, restricting MCPyV DNA replication. SCF E3 ubiquitin ligases require their substrates to be phosphorylated to bind them, utilizing phosphorylated serine residues as docking sites. The MCPyV LT unique region (MUR) is highly phosphorylated and plays a role in multiple host protein interactions, including SCF E3 ubiquitin ligases. Therefore, this domain highly governs LT stability. Though much work has been conducted to identify host factors that restrict MCPyV LT protein expression, the kinase(s) that cooperates with the SCF E3 ligase remains unknown. Here, we demonstrate that casein kinase 1 alpha (CK1\u03b1) negatively regulates MCPyV LT stability and LT-mediated replication by modulating interactions with the SCF \u03b2-TrCP. Specifically, we show that numerous CK1 isoforms (\u03b1, \u03b4, \u03b5) localize in close proximity to MCPyV LT through\n                      <jats:italic toggle=\"yes\">in situ<\/jats:italic>\n                      proximity ligation assays (PLA) and CK1\u03b1 overexpression mainly resulted in decreased MCPyV LT protein expression. Inhibition of CK1\u03b1 using short hairpin RNA (shRNA) and treatment of a CK1\u03b1 inhibitor or an mTOR inhibitor, TORKinib, resulted in decreased \u03b2-TrCP interaction with LT, increased LT expression, and enhanced MCPyV replication. The expression level of the\n                      <jats:italic toggle=\"yes\">CSNK1A1<\/jats:italic>\n                      gene transcripts is higher in MCPyV-positive MCC, suggesting a vital role of CK1\u03b1 in limiting MCPyV replication required for establishing persistent infection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Merkel cell polyomavirus (MCPyV) large tumor antigen is a polyphosphoprotein and the phosphorylation event is required to modulate various functions of LT, including viral replication. Therefore, cellular kinase pathways are indispensable for governing MCPyV polyomavirus infection and life cycle in coordinating with the immunosuppression environment at disease onset. Understanding the regulation mechanisms of MCPyV replication by viral and cellular factors will guide proper prevention strategies with targeted inhibitors for MCPyV-associated Merkel cell carcinoma (MCC) patients, who currently lack therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01117-24","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T09:05:39Z","timestamp":1719565539000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Casein kinase 1\u03b1 mediates phosphorylation of the Merkel cell polyomavirus large T antigen for \u03b2-TrCP destruction complex interaction and subsequent degradation"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8867-9596","authenticated-orcid":false,"given":"Alexander M.","family":"Pham","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Penn State College of Medicine","place":["Hershey, USA"]},{"name":"Penn State Cancer Institute","place":["Hershey, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-746X","authenticated-orcid":true,"given":"Hyun Jin","family":"Kwun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Penn State College of Medicine","place":["Hershey, USA"]},{"name":"Penn State Cancer Institute","place":["Hershey, 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