Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor

Yan Yang, Yuqiong Liang, Lin Qu, Zeming Chen, Min Kyung Yi, Kui Li, Stanley M. Lemon

Research output: Contribution to journalArticlepeer-review

217 Scopus citations

Abstract

Mitochondrial antiviral signaling protein (MAVS) is an essential component of virus-activated signaling pathways that induce protective IFN responses. Its localization to the outer mitochondrial membrane suggests an important yet unexplained role for mitochondria in innate immunity. Here, we show that hepatitis A virus (HAV), a hepatotropic picornavirus, ablates type 1 IFN responses by targeting the 3ABC precursor of its 3Cpro cysteine protease to mitochondria where it colocalizes with and cleaves MAVS, thereby disrupting activation of IRF3 through the MDA5 pathway. The 3ABC cleavage of MAVS requires both the protease activity of 3Cpro and a transmembrane domain in 3A that directs 3ABC to mitochondria. Lacking this domain, mature 3Cpro protease is incapable of MAVS proteolysis. HAV thus disrupts host signaling by a mechanism that parallels that of the serine NS3/4A protease of hepatitis C virus, but differs in its use of a stable, catalytically active polyprotein processing intermediate. The unique requirement for mitochondrial localization of 3ABC underscores the importance of mitochondria to host control of virus infections within the liver.

Original languageEnglish (US)
Pages (from-to)7253-7258
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number17
DOIs
StatePublished - Apr 24 2007

Keywords

  • Hepatitis virus
  • Interferon regulatory factor 3
  • Interferon-beta
  • Melanoma differentiation associated gene 5
  • Mitochondrial antiviral signaling protein

ASJC Scopus subject areas

  • General

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