한빛사논문
- 조회225
Lisa Goers 1,2, Kyungsub Kim 1,2, Teagan C Stedman 1, Patrick J Canning 1, Xiangyu Mou 1,2, Nadja Heinz Ernst 1,2, Jörn Coers 3,4, Cammie F Lesser 1,2,5,6
1Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02115.
2Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
3Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27110.
4Department of Immunology, Duke University Medical Center, Durham, NC 27110.
5Broad Institute of Massachusetts General Hospital and Harvard, Cambridge, MA 02142.
6Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139.
L.G. and K.K. contributed equally to this work.
To whom correspondence may be addressed.: Cammie F Lesser
Abstract
Pyroptosis is an inflammatory form of cell death induced upon recognition of invading microbes. During an infection, pyroptosis is enhanced in interferon-gamma-exposed cells via the actions of members of the guanylate-binding protein (GBP) family. GBPs promote caspase-4 (CASP4) activation by enhancing its interactions with lipopolysaccharide (LPS), a component of the outer envelope of Gram-negative bacteria. Once activated, CASP4 promotes the formation of noncanonical inflammasomes, signaling platforms that mediate pyroptosis. To establish an infection, intracellular bacterial pathogens, like Shigella species, inhibit pyroptosis. The pathogenesis of Shigella is dependent on its type III secretion system, which injects ~30 effector proteins into host cells. Upon entry into host cells, Shigella are encapsulated by GBP1, followed by GBP2, GBP3, GBP4, and in some cases, CASP4. It has been proposed that the recruitment of CASP4 to bacteria leads to its activation. Here, we demonstrate that two Shigella effectors, OspC3 and IpaH9.8, cooperate to inhibit CASP4-mediated pyroptosis. We show that in the absence of OspC3, an inhibitor of CASP4, IpaH9.8 inhibits pyroptosis via its known degradation of GBPs. We find that, while some LPS is present within the host cell cytosol of epithelial cells infected with wild-type Shigella, in the absence of IpaH9.8, increased amounts are shed in a GBP1-dependent manner. Furthermore, we find that additional IpaH9.8 targets, likely GBPs, promote CASP4 activation, even in the absence of GBP1. These observations suggest that by boosting LPS release, GBP1 provides CASP4-enhanced access to cytosolic LPS, thus promoting host cell death via pyroptosis.
논문정보
- Research article
- 2023년 04월 (BRIC 등록일 2023-04-14)
- 국외 연구진
- 생명과학 > 분자생물학
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