Functional characterization of domains of IPS-1 using an inducible oligomerization system.

The innate immune system recognizes viral nucleic acids and stimulates cellular antiviral responses. Intracellular detection of viral RNA is mediated by the Retinoic acid inducible gene (RIG)-I Like Receptor (RLR), leading to production of type I interferon (IFN) and pro-inflammatory cytokines. Once...

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Autores principales:	Shiori Takamatsu, Kazuhide Onoguchi, Koji Onomoto, Ryo Narita, Kiyohiro Takahasi, Fumiyoshi Ishidate, Takahiro K Fujiwara, Mitsutoshi Yoneyama, Hiroki Kato, Takashi Fujita
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/64fceae48bba4d2698d93f9505f2a71b
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spelling	oai:doaj.org-article:64fceae48bba4d2698d93f9505f2a71b2021-11-18T08:02:27ZFunctional characterization of domains of IPS-1 using an inducible oligomerization system.1932-620310.1371/journal.pone.0053578https://doaj.org/article/64fceae48bba4d2698d93f9505f2a71b2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23308256/?tool=EBIhttps://doaj.org/toc/1932-6203The innate immune system recognizes viral nucleic acids and stimulates cellular antiviral responses. Intracellular detection of viral RNA is mediated by the Retinoic acid inducible gene (RIG)-I Like Receptor (RLR), leading to production of type I interferon (IFN) and pro-inflammatory cytokines. Once cells are infected with a virus, RIG-I and MDA5 bind to viral RNA and undergo conformational change to transmit a signal through direct interaction with downstream CARD-containing adaptor protein, IFN-β promoter stimulator-1 (IPS-1, also referred as MAVS/VISA/Cardif). IPS-1 is composed of N-terminal Caspase Activation and Recruitment Domain (CARD), proline-rich domain, intermediate domain, and C-terminal transmembrane (TM) domain. The TM domain of IPS-1 anchors it to the mitochondrial outer membrane. It has been hypothesized that activated RLR triggers the accumulation of IPS-1, which forms oligomer as a scaffold for downstream signal proteins. However, the exact mechanisms of IPS-1-mediated signaling remain controversial. In this study, to reveal the details of IPS-1 signaling, we used an artificial oligomerization system to induce oligomerization of IPS-1 in cells. Artificial oligomerization of IPS-1 activated antiviral signaling without a viral infection. Using this system, we investigated the domain-requirement of IPS-1 for its signaling. We discovered that artificial oligomerization of IPS-1 could overcome the requirement of CARD and the TM domain. Moreover, from deletion- and point-mutant analyses, the C-terminal Tumor necrosis factor Receptor-Associated Factor (TRAF) binding motif of IPS-1 (aa. 453-460) present in the intermediate domain is critical for downstream signal transduction. Our results suggest that IPS-1 oligomerization is essential for the formation of a multiprotein signaling complex and enables downstream activation of transcription factors, Interferon Regulatory Factor 3 (IRF3) and Nuclear Factor-κB (NF-κB), leading to type I IFN and pro-inflammatory cytokine production.Shiori TakamatsuKazuhide OnoguchiKoji OnomotoRyo NaritaKiyohiro TakahasiFumiyoshi IshidateTakahiro K FujiwaraMitsutoshi YoneyamaHiroki KatoTakashi FujitaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e53578 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shiori Takamatsu Kazuhide Onoguchi Koji Onomoto Ryo Narita Kiyohiro Takahasi Fumiyoshi Ishidate Takahiro K Fujiwara Mitsutoshi Yoneyama Hiroki Kato Takashi Fujita Functional characterization of domains of IPS-1 using an inducible oligomerization system.
description	The innate immune system recognizes viral nucleic acids and stimulates cellular antiviral responses. Intracellular detection of viral RNA is mediated by the Retinoic acid inducible gene (RIG)-I Like Receptor (RLR), leading to production of type I interferon (IFN) and pro-inflammatory cytokines. Once cells are infected with a virus, RIG-I and MDA5 bind to viral RNA and undergo conformational change to transmit a signal through direct interaction with downstream CARD-containing adaptor protein, IFN-β promoter stimulator-1 (IPS-1, also referred as MAVS/VISA/Cardif). IPS-1 is composed of N-terminal Caspase Activation and Recruitment Domain (CARD), proline-rich domain, intermediate domain, and C-terminal transmembrane (TM) domain. The TM domain of IPS-1 anchors it to the mitochondrial outer membrane. It has been hypothesized that activated RLR triggers the accumulation of IPS-1, which forms oligomer as a scaffold for downstream signal proteins. However, the exact mechanisms of IPS-1-mediated signaling remain controversial. In this study, to reveal the details of IPS-1 signaling, we used an artificial oligomerization system to induce oligomerization of IPS-1 in cells. Artificial oligomerization of IPS-1 activated antiviral signaling without a viral infection. Using this system, we investigated the domain-requirement of IPS-1 for its signaling. We discovered that artificial oligomerization of IPS-1 could overcome the requirement of CARD and the TM domain. Moreover, from deletion- and point-mutant analyses, the C-terminal Tumor necrosis factor Receptor-Associated Factor (TRAF) binding motif of IPS-1 (aa. 453-460) present in the intermediate domain is critical for downstream signal transduction. Our results suggest that IPS-1 oligomerization is essential for the formation of a multiprotein signaling complex and enables downstream activation of transcription factors, Interferon Regulatory Factor 3 (IRF3) and Nuclear Factor-κB (NF-κB), leading to type I IFN and pro-inflammatory cytokine production.
format	article
author	Shiori Takamatsu Kazuhide Onoguchi Koji Onomoto Ryo Narita Kiyohiro Takahasi Fumiyoshi Ishidate Takahiro K Fujiwara Mitsutoshi Yoneyama Hiroki Kato Takashi Fujita
author_facet	Shiori Takamatsu Kazuhide Onoguchi Koji Onomoto Ryo Narita Kiyohiro Takahasi Fumiyoshi Ishidate Takahiro K Fujiwara Mitsutoshi Yoneyama Hiroki Kato Takashi Fujita
author_sort	Shiori Takamatsu
title	Functional characterization of domains of IPS-1 using an inducible oligomerization system.
title_short	Functional characterization of domains of IPS-1 using an inducible oligomerization system.
title_full	Functional characterization of domains of IPS-1 using an inducible oligomerization system.
title_fullStr	Functional characterization of domains of IPS-1 using an inducible oligomerization system.
title_full_unstemmed	Functional characterization of domains of IPS-1 using an inducible oligomerization system.
title_sort	functional characterization of domains of ips-1 using an inducible oligomerization system.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/64fceae48bba4d2698d93f9505f2a71b
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Functional characterization of domains of IPS-1 using an inducible oligomerization system.

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