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

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 associa...

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Autores principales: Wang, Ling, Howell, Mary E.A., McPeak, Brooke, Riggs, Katrina, Kohne, Carissa, Yohanon, Jether Uel, Foxler, Daniel E., Sharp, Tyson V., Moorman, Jonathan P., Yao, Zhi Q., Ning, Shunbin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814212/
https://www.ncbi.nlm.nih.gov/pubmed/29464072
http://dx.doi.org/10.18632/oncotarget.23676
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author Wang, Ling
Howell, Mary E.A.
McPeak, Brooke
Riggs, Katrina
Kohne, Carissa
Yohanon, Jether Uel
Foxler, Daniel E.
Sharp, Tyson V.
Moorman, Jonathan P.
Yao, Zhi Q.
Ning, Shunbin
author_facet Wang, Ling
Howell, Mary E.A.
McPeak, Brooke
Riggs, Katrina
Kohne, Carissa
Yohanon, Jether Uel
Foxler, Daniel E.
Sharp, Tyson V.
Moorman, Jonathan P.
Yao, Zhi Q.
Ning, Shunbin
author_sort Wang, Ling
collection PubMed
description 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.
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spelling pubmed-58142122018-02-20 LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death Wang, Ling Howell, Mary E.A. McPeak, Brooke Riggs, Katrina Kohne, Carissa Yohanon, Jether Uel Foxler, Daniel E. Sharp, Tyson V. Moorman, Jonathan P. Yao, Zhi Q. Ning, Shunbin Oncotarget Research Paper 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. Impact Journals LLC 2017-12-26 /pmc/articles/PMC5814212/ /pubmed/29464072 http://dx.doi.org/10.18632/oncotarget.23676 Text en Copyright: © 2018 Wang et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Wang, Ling
Howell, Mary E.A.
McPeak, Brooke
Riggs, Katrina
Kohne, Carissa
Yohanon, Jether Uel
Foxler, Daniel E.
Sharp, Tyson V.
Moorman, Jonathan P.
Yao, Zhi Q.
Ning, Shunbin
LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death
title LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death
title_full LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death
title_fullStr LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death
title_full_unstemmed LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death
title_short LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death
title_sort limd1 is induced by and required for lmp1 signaling, and protects ebv-transformed cells from dna damage-induced cell death
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814212/
https://www.ncbi.nlm.nih.gov/pubmed/29464072
http://dx.doi.org/10.18632/oncotarget.23676
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