Viral interferon regulatory factor 1 of Kaposi's sarcoma-associated herpesvirus interacts with a cell death regulator, GRIM19, and inhibits interferon/retinoic acid-induced cell death.

in Journal of virology by Taegun Seo, Daeyoup Lee, Young Sam Shim, Jon E Angell, Natesa V Chidambaram, Dhananjaya V Kalvakolanu, Joonho Choe

TLDR

  • The study found that a protein called vIRF1 from a virus called KSHV helps cells become cancerous by interacting with a protein called GRIM19. The study also found that another protein called E6 from a different virus called HPV also interacts with GRIM19. The study suggests that vIRF1 and E6 could be targeted for treatment of viral infections and cancer caused by these viruses.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) plays a significant role in the development of Kaposi's sarcoma, primary effusion lymphoma, and some forms of multicentric Castleman's disease. The KSHV open reading frame K9 encodes the viral interferon (IFN) factor 1 (vIRF1), which downregulates IFN- and IRF-mediated transcriptional activation, and leads to cellular transformation in rodent fibroblasts and induction of tumors in nude mice. Using the yeast two-hybrid assay, we identified genes associated with retinoid-IFN-induced mortality-19 (GRIM19), which interacts directly with vIRF1, both in vivo and in vitro. The N-terminal region of vIRF1 is required for binding GRIM19. Colocalization of vIRF1 and GRIM19 was observed in 293T cells. The vIRF1 protein deregulates GRIM19-induced apoptosis in the presence of IFN/all-trans-retinoic acid (RA) and inhibits IFN/RA-induced cell death. Another DNA tumor viral protein, human papillomavirus type 16 E6, also binds GRIM19, suggesting that this is a general target of viral proteins. Our results collectively indicate that vIRF1 modulates IFN/RA-cell death signals via interactions with GRIM19.

Overview

  • The study focuses on the role of Kaposi's sarcoma-associated herpesvirus (KSHV) in the development of Kaposi's sarcoma, primary effusion lymphoma, and some forms of multicentric Castleman's disease. The study aims to identify genes associated with retinoid-IFN-induced mortality-19 (GRIM19), which interacts directly with vIRF1, and to investigate how vIRF1 modulates IFN/RA-cell death signals via interactions with GRIM19. The study uses the yeast two-hybrid assay and colocalization studies in 293T cells to identify and validate the interaction between vIRF1 and GRIM19. The study also investigates the role of vIRF1 in regulating GRIM19-induced apoptosis in the presence of IFN/all-trans-retinoic acid (RA) and inhibiting IFN/RA-induced cell death. The study aims to provide insights into the mechanisms underlying the development of KSHV-associated diseases and to identify potential targets for therapeutic interventions. The hypothesis being tested is that vIRF1 modulates IFN/RA-cell death signals via interactions with GRIM19.

Comparative Analysis & Findings

  • The study identifies genes associated with retinoid-IFN-induced mortality-19 (GRIM19), which interacts directly with vIRF1, both in vivo and in vitro. The study also investigates the role of vIRF1 in regulating GRIM19-induced apoptosis in the presence of IFN/all-trans-retinoic acid (RA) and inhibiting IFN/RA-induced cell death. The study finds that vIRF1 modulates IFN/RA-cell death signals via interactions with GRIM19. The study also finds that human papillomavirus type 16 E6 binds GRIM19, suggesting that this is a general target of viral proteins. The study identifies a novel mechanism by which vIRF1 regulates cell death signals and provides insights into the mechanisms underlying the development of KSHV-associated diseases.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies a novel mechanism by which vIRF1 regulates cell death signals, which could be targeted for therapeutic interventions. The study also identifies a general target of viral proteins, which could be targeted for the treatment of viral infections. The study suggests future research directions, such as investigating the role of vIRF1 in regulating cell death signals in other viral infections and identifying other targets of vIRF1. The study also suggests future research directions, such as investigating the role of GRIM19 in the development of KSHV-associated diseases and identifying other genes that interact with vIRF1. The study's findings have the potential to advance our understanding of the mechanisms underlying the development of viral infections and to identify new targets for therapeutic interventions.
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