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

doi:10.1073/pnas.0611506104

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

Center for Hepatitis Research, Institute for Human Infections and Immunity, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1019

Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved March 12, 2007 (received for review December 22, 2006)

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 3C^pro 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 3C^pro and a transmembrane domain in 3A that directs 3ABC to mitochondria. Lacking this domain, mature 3C^pro 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.

Footnotes

^‡To whom correspondence should be addressed. E-mail: smlemon{at}utmb.edu
Author contributions: Y.Y., Y.L., and L.Q. contributed equally to this work; Y.Y., Y.L., L.Q., Z.C., M.Y., K.L., and S.M.L. designed research; Y.Y., Y.L., L.Q., Z.C., and M.Y. performed research; Y.Y., Y.L., L.Q., Z.C., M.Y., K.L., and S.M.L. analyzed data; and Y.Y., Y.L., K.L., and S.M.L. wrote the paper.
↵ ^†Present address: University of Texas M.D. Anderson Cancer Center, Houston, TX 77030.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0611506104/DC1.
Abbreviations:

RIG-I,

retinoic acid-inducible gene I;

CARD,

caspase-recruitment domain;

MAVS,

mitochondrial antiviral signaling protein;

MDA5,

melenoma differentation associated gene 5;

HCV,

hepatitis C virus;

HAV,

hepatitis A virus;

TM,

transmembrane;

SenV,

Sendai virus.