Guanylate binding proteins promote caspase-11–dependent pyroptosis in response to cytoplasmic LPS

Abstract

Significance A major component of the cell envelope of Gram-negative bacteria is LPS, also known as endotoxin. LPS produced during bacterial infections triggers inflammation, which can lead to septic shock and death. Our immune system can recognize LPS both outside and inside of cells. The recognition of extracellular and vacuolar LPS by LPS binding proteins is well described, but little is known about the recognition of cytoplasmic LPS. Here, we show that cytoplasmic LPS derived from the intracellular bacterial pathogen Legionella activated a proinflammatory immune response. We further identified host guanylate binding proteins as critical mediators of immunity triggered by cytoplasmic LPS. These findings are likely to advance our understanding of how cells can sense intracellular LPS.

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

“…Indeed, GBPs function as sensors of endolysosomal membrane integrity (56) and play an important role during both canonical and noncanonical inflammasome activation in response to infection by Gram-negative bacteria. GBPs can contribute to inflammasome activation by binding to and disrupting pathogen-containing vacuoles or bacteria themselves, thus enabling the detection of cytoplasmic LPS (28,34,(61)(62)(63). Whether GBPs might be recruited to vacuoles containing translocated microbial products but not pathogens themselves has not been investigated.…”

“…However, GBPs can also promote the activation of caspase-11 independent of direct vacuolar lysis in the case of Legionella or Chlamydia (28,33). In support of their lysis-independent function, GBPs were demonstrated to be important for noncanonical inflammasome activation in response to transfection of LPS into the cytosol (28).…”

“…Caspase-11-dependent cleavage of GSDMD and subsequent pore formation also triggers activation of the canonical NLRP3 inflammasome by inducing potassium efflux (22)(23)(24). Caspase-11 activation can also be triggered by endocytosis of Gram-negative bacterial outer membrane vesicles (25), the activity of type III and type IV secretion systems of Gram-negative pathogens like Legionella and Yersinia (26,27), or disruption of bacterial cell-containing vacuolar compartments by members of the interferon (IFN)-inducible GTPases known as guanylate binding proteins (GBPs) (28)(29)(30)(31)(32).…”

“…GBPs encoded on chromosome 3 (Gbp Chr3 ) are necessary for maximal noncanonical inflammasome activation in response to vacuolar Gram-negative bacteria, cytosolic lipopolysaccharide (LPS), or entry of Gram-negative bacteria into the cytosol (28,33,34). GBPs have been described to function by lysing Salmonella-containing vacuoles and exposing Salmonella LPS to the host cell cytosol, where it is detected by caspase-11 (34).…”

“…A recent study also revealed that the GBPs recruit the immunity-related GTPase (IRG) protein IRGB10 to the surface of cytosolic bacteria, leading to bacterial lysis and activation of both canonical and noncanonical inflammasomes (35). However, GBPs can also promote the activation of caspase-11 independent of direct vacuolar lysis in the case of Legionella or Chlamydia (28,33). In support of their lysis-independent function, GBPs were demonstrated to be important for noncanonical inflammasome activation in response to transfection of LPS into the cytosol (28).…”