Abstract
p18 is a key negative regulator of cell cycle progression and mediates cell cycle arrest at the G1/S phase. Ubiquitination is the prime mechanism in regulating p18 protein abundance. However, so far no post- translational regulator, especially DUBs, has been identified to regulate the protein stability of p18. In this paper, we identified CYLD as a deubiquitinase of p18, which binds to and removes the K48-linked polyubiquitylation chains conjugated onto p18, thus stabilizing the p18 protein. Loss of CYLD causes the degradation of p18 and induces the G1/S transition. Epstein–Barr virus (EBV), is the human oncovirus etiologically linked to nasopharyngeal carcinoma (NPC). Here we found that EBV drives a replication passive environment by deregulating the CYLD-p18 axis. Functionally, CYLD inhibits cell proliferation and tumorigenesis through p18 in vivo. Restoring CYLD prevents EBV induced viral replication and tumor growth. Collectively, our results identify CYLD directly stabilizes p18 to regulate the cellular G1/S transition. The reconstitution of CYLD-p18 axis could be a promising approach for EBV-positive cancer therapy.
Highlights
Cyclin-dependent kinase inhibitors (CKIs) are key negative regulators in cell cycle progression, they bind to cyclindependent kinases (CDKs) and block their association with cyclins[1,2]
CKIs from the INK4 family interact with CDK4 or CDK6, and prevent the activation of the cyclin D/CDK4/6 kinases, resulting in decreased Rb phosphorylation, thereby inhibiting E2F transcription factors to activate the transcription of a plethora of genes involved in cell cycle progression from G1 into S phase[1,5]
Posttranslational modification mechanisms involving the ubiquitinproteasome pathway are the dominant mechanisms in regulating protein abundance of CKIs, and the same is true of p1834
Summary
Cyclin-dependent kinase inhibitors (CKIs) are key negative regulators in cell cycle progression, they bind to cyclindependent kinases (CDKs) and block their association with cyclins[1,2]. Transcriptional activator Zta(BZLF1), together with EBV replication proteins like EAD(BMRF1) and BALF2/5 induce intense viral DNA replication and over 80 viral proteins are expressed in this stage[27]. This reactivation corresponds with the emergence of human cancers and antibodies targeting early lytic proteins, including. We that directly cleaves polyubiquitination chains of p18 and performed GSEA (Gene Set Enrichment Analysis) using 31 NPC stabilizes its protein level, thereby negatively regulating cell cycle data sets (GES12452) focusing on genes in cell signaling pathways. Tion of the host cell cycle machinery to promote replication of we examined the effects of CYLD expression on EBV (+) cell viral DNA.
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