RT Journal Article
SR Electronic
T1 Caspase-1 interdomain linker cleavage is required for pyroptosis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000664
DO 10.26508/lsa.202000664
VO 3
IS 3
A1 Ball, Daniel P
A1 Taabazuing, Cornelius Y
A1 Griswold, Andrew R
A1 Orth, Elizabeth L
A1 Rao, Sahana D
A1 Kotliar, Ilana B
A1 Vostal, Lauren E
A1 Johnson, Darren C
A1 Bachovchin, Daniel A
YR 2020
UL http://www.life-science-alliance.org/content/3/3/e202000664.abstract
AB Pathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied inflammasome-forming PRRs oligomerize with the adapter protein ASC (apoptosis-associated speck-like protein containing a CARD) to generate a large structure in the cytosol, which induces the dimerization, autoproteolysis, and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming smaller “ASC-independent” inflammasomes. It is currently thought that little, if any, pro-caspase-1 autoproteolysis occurs during, and is not required for, ASC-independent inflammasome signaling. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first canonical inflammasome-forming PRR that does not form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is a required regulatory step for pyroptosis induced by human canonical inflammasomes.