Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases.

Etienne Meunier, Mathias S. Dick,        Roland F. Dreier, Nura Schürmann, Daniela Kenzelmann Broz, Søren Warming, Merone Roose-Girma, Dirk Bumann, Nobuhiko Kayagaki, Kiyoshi Takeda, Masahiro Yamamoto & Petr Broz.

Nature. (2014) 509, 366–370

Speaker: Chen-Chu Kao (高禎鞠)                                Time: 14:00~15:00, Oct 15, 2014

Commentator: Dr. Pei-Jane Tsai (蔡佩珍 老師)        

Place: Room 601

Abstract:

Septic shock syndrome is a widespread and uncontrolled inflammatory state resulting from a systemic response to bacterial infection. Canonical inflammasome activation result in caspase-1 activation, which leads to maturation and secretion of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and causes programmed form of cell death called pyroptosis. The previous study showed that lipopolysaccharide (LPS) from Gram-negative bacteria triggers “non-canonical inflammasome”, which the caspase-11 is activated, yielding two functional changes: activation of caspase-1 which in turn activates IL-1β and IL-18, and caspase-11-dependent pyroptosis and IL-1α release¹. In mouse macrophages, TIR domain-containing adaptor protein inducing IFN-β (TRIF; also known as TICAM1) is essential for caspase-11-dependent cell death by Gram-negative bacteria², indicating that interferon-induced genes (ISGs) is required for initiating this pathway. However, the roles of ISGs involved in this innate immune system have not been identified. Here this study shows that guanylate-binding protein (Gbp) gene family, as part of IFN-γ–inducibleguanosine triphosphatase (GTPase) superfamily, is required for the non-canonical inflammasome activation during vacuolar Gram-negative bacteria infection. Caspase-11 activation relies on GBPs, which are recruited to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus facilitating the recognition of their LPS by an unidentified cytosolic sensor. Moreover, GBPs recruit the danger sensor galectin-8 to contain bacteria in autophagosomes and limit caspase-11 activation. These findings indicate that GBP-mediated lysis of pathogen-containing vacuoles facilitates non-canonical inflammasome activation and autophagy-mediated clearance of the intracellular bacterial pathogens prevents excessive induction of the inflammatory innate immune response.

References:

1          Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117-121, doi:10.1038/nature10558 (2011).

2          Rathinam, V. A. et al. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150, 606-619, doi:10.1016/j.cell.2012.07.007 (2012).