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Detecting lipopolysaccharide in the cytosol of mammalian cells: Lessons from MD‐2/TLR4
Author(s) -
Barker Jason H.,
Weiss Jerrold P.
Publication year - 2019
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.3mir1118-434r
Subject(s) - tlr4 , proinflammatory cytokine , inflammasome , lipopolysaccharide , cytosol , biology , microbiology and biotechnology , caspase , innate immune system , extracellular , caspase 1 , inflammation , immune system , apoptosis , immunology , biochemistry , programmed cell death , signal transduction , enzyme
Abstract Proinflammatory immune responses to Gram‐negative bacterial lipopolysaccharides (LPS) are crucial to innate host defenses but can also contribute to pathology. How host cells sensitively detect structural features of LPS was a mystery for years, especially given that a portion of the molecule essential for its potent proinflammatory properties—lipid A—is buried in the bacterial membrane. Studies of responses to extracellular and vacuolar LPS revealed a crucial role for accessory proteins that specifically bind LPS‐rich membranes and extract LPS monomers to generate a complex of LPS, MD‐2, and TLR4. These insights provided means to understand better both the remarkable host sensitivity to LPS and the means whereby specific LPS structural features are discerned. More recently, the noncanonical inflammasome, consisting of caspases‐4/5 in humans and caspase‐11 in mice, has been demonstrated to mediate responses to LPS that has reached the host cytosol. Precisely how LPS gains access to cytosolic caspases—and in what form—is not well characterized, and understanding this process will provide crucial insights into how the noncanonical inflammasome is regulated during infection. Herein, we briefly review what is known about LPS detection by cytosolic caspases‐4/5/11, focusing on lessons derived from studies of the better‐characterized TLR4 system that might direct future mechanistic questions.