LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death.

Autor:	Wang L; Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA.; Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA., Howell MEA; Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA., McPeak B; Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA., Riggs K; Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA., Kohne C; Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA., Yohanon JU; Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA., Foxler DE; Centre for Molecular Oncology, Barts Cancer Institute, University of London, London EC1M 6BQ, UK., Sharp TV; Centre for Molecular Oncology, Barts Cancer Institute, University of London, London EC1M 6BQ, UK., Moorman JP; Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA.; Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA.; Hepatitis (HCV/HIV) Program, James H Quillen VA Medical Center, Johnson City 37614, TN, USA., Yao ZQ; Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA.; Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA.; Hepatitis (HCV/HIV) Program, James H Quillen VA Medical Center, Johnson City 37614, TN, USA., Ning S; Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA.; Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City 37614, TN, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2017 Dec 26; Vol. 9 (5), pp. 6282-6297. Date of Electronic Publication: 2017 Dec 26 (Print Publication: 2018).
DOI:	10.18632/oncotarget.23676
Abstrakt:	LIMD1 (LIM domain-containing protein 1) is considered as a tumor suppressor, being deregulated in many cancers to include hematological malignancies; however, very little is known about the underlying mechanisms of its deregulation and its roles in carcinogenesis. Epstein-Barr Virus (EBV) is associated with a panel of malignancies of lymphocytic and epithelial origin. Using high throughput expression profiling, we have previously identified LIMD1 as a common marker associated with the oncogenic transcription factor IRF4 in EBV-related lymphomas and other hematological malignancies. In this study, we have identified potential conserved IRF4- and NFκB-binding motifs in the LIMD1 gene promoter, and both are demonstrated functional by promoter-reporter assays. We further show that LIMD1 is partially upregulated by EBV latent membrane protein 1 (LMP1) via IRF4 and NFκB in EBV latency. As to its role in the setting of EBV latent infection, we show that LIMD1 interacts with TRAF6, a crucial mediator of LMP1 signal transduction. Importantly, LIMD1 depletion impairs LMP1 signaling and functions, potentiates ionomycin-induced DNA damage and apoptosis, and inhibits p62-mediated selective autophagy. Taken together, these results show that LIMD1 is upregulated in EBV latency and plays an oncogenic role rather than that of a tumor suppressor. Our findings have identified LIMD1 as a novel player in EBV latency and oncogenesis, and open a novel research avenue, in which LIMD1 and p62 play crucial roles in linking DNA damage response (DDR), apoptosis, and autophagy and their potential interplay during viral oncogenesis. Competing Interests: CONFLICTS OF INTEREST None.
Databáze:	MEDLINE
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