TY - JOUR
T1 - The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation
AU - Ratsimandresy, Rojo A.
AU - Chu, Lan H.
AU - Khare, Sonal
AU - De Almeida, Lucia
AU - Gangopadhyay, Anu
AU - Indramohan, Mohanalaxmi
AU - Misharin, Alexander V.
AU - Greaves, David R.
AU - Perlman, Harris
AU - Dorfleutner, Andrea
AU - Stehlik, Christian
N1 - Funding Information:
This work was supported by the National Institutes of Health (AI099009, AR064349 and AI120618 to C.S., AI120625 to C.S. and A.D. and AR066739 to A.D.), a Cancer Center Support Grant (CA060553), the Skin Disease Research Center (AR057216) to C.S. and The British Heart Foundation (RG/15/10/31485) to D.R.G. L.H.C. was supported by the Vietnam Education Foundation Fellowship and the American Heart Association (AHA, 15PRE25700116), S.K. was an Arthritis Foundation fellow (AF161715), L.d.A. was supported by the AHA (11POST585000) and the NIH (T32AR007611 and AR064349S1) and M.I. was supported by the AHA (15POST25690052). This work was supported by the Northwestern University Transgenic and Targeted Mutagenesis Laboratory, Pathology core, Center for Advanced Microscopy and Flow Cytometry core facility.
Publisher Copyright:
© The Author(s) 2017.
PY - 2017/6/5
Y1 - 2017/6/5
N2 - Inflammasomes are protein platforms linking recognition of microbe, pathogen-associated and damage-associated molecular patterns by cytosolic sensory proteins to caspase-1 activation. Caspase-1 promotes pyroptotic cell death and the maturation and secretion of interleukin (IL)-1β and IL-18, which trigger inflammatory responses to clear infections and initiate wound-healing; however, excessive responses cause inflammatory disease. Inflammasome assembly requires the PYRIN domain (PYD)-containing adaptor ASC, and depends on PYD-PYD interactions. Here we show that the PYD-only protein POP2 inhibits inflammasome assembly by binding to ASC and interfering with the recruitment of ASC to upstream sensors, which prevents caspase-1 activation and cytokine release. POP2 also impairs macrophage priming by inhibiting the activation of non-canonical IκB kinase ϵ and IκBα, and consequently protects from excessive inflammation and acute shock in vivo. Our findings advance our understanding of the complex regulatory mechanisms that maintain a balanced inflammatory response and highlight important differences between individual POP members.
AB - Inflammasomes are protein platforms linking recognition of microbe, pathogen-associated and damage-associated molecular patterns by cytosolic sensory proteins to caspase-1 activation. Caspase-1 promotes pyroptotic cell death and the maturation and secretion of interleukin (IL)-1β and IL-18, which trigger inflammatory responses to clear infections and initiate wound-healing; however, excessive responses cause inflammatory disease. Inflammasome assembly requires the PYRIN domain (PYD)-containing adaptor ASC, and depends on PYD-PYD interactions. Here we show that the PYD-only protein POP2 inhibits inflammasome assembly by binding to ASC and interfering with the recruitment of ASC to upstream sensors, which prevents caspase-1 activation and cytokine release. POP2 also impairs macrophage priming by inhibiting the activation of non-canonical IκB kinase ϵ and IκBα, and consequently protects from excessive inflammation and acute shock in vivo. Our findings advance our understanding of the complex regulatory mechanisms that maintain a balanced inflammatory response and highlight important differences between individual POP members.
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U2 - 10.1038/ncomms15556
DO - 10.1038/ncomms15556
M3 - Article
C2 - 28580931
AN - SCOPUS:85020379250
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 15556
ER -