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

Ling Wang,Zhi Q Yao,Katrina Riggs,Jonathan P Moorman,Brooke Mcpeak,Carissa Kohne,Mary E.A Howell,Shunbin Ning,Tyson V Sharp,Daniel E Foxler,Jether Uel Yohanon

doi:10.18632/oncotarget.23676

Abstract

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.

Highlights

Epstein-Barr Virus (EBV) infection is associated with more than 50% of AIDS-related lymphomas (ARLs) and other malignancies such as nasopharyngeal carcinoma, up to 400 thousand cases each year as estimated by the World Health Organization (WHO) [1]
We further show that LIM domain-containing protein 1 (LIMD1) is required for latent membrane protein 1 (LMP1) signal transduction and function
Promoter-reporter assay results further showed that interferon regulatory factor 4 (IRF4), NFκB or LMP1 alone can activate the human LIMD1 promoter, but IRF7 had no significant effect on it (Figure 1B)

Summary

Introduction

Epstein-Barr Virus (EBV) infection is associated with more than 50% of AIDS-related lymphomas (ARLs) and other malignancies such as nasopharyngeal carcinoma, up to 400 thousand cases each year as estimated by the World Health Organization (WHO) [1]. LMP1 oncogenicity is attributed by its ability to activate multiple oncogenic transcription factors, including NFκB that interacts with other EBV oncoproteins to form viral super-enhancers to regulate expression of a large scale of host genes involved in lymphoblastoid B-cell growth and survival [3]. Like the oncogenic transcription factor interferon regulatory factor 4 (IRF4), overexpression of LIMD1 is a hallmark of ABC subtype of diffuse large B cell lymphoma (DLBCL) [5]. LIMD1 is involved in the assembly of numerous protein complexes by acting as an adaptor protein that interacts with various proteins such as Rb [6], TRAF6 [7], p62/SQSTM1 [8], VHL and PHD [9, 10], and LATS and WW45 [11], and participates in myriad cellular processes including cell fate determination, cytoskeletal organization, osteoclastogenesis [8], repression of gene transcription, cell-cell adhesion, cell differentiation, proliferation and migration. The mechanisms underlying its regulation and its role in the setting of EBV infection remain uninvestigated

Methods

Results

Conclusion