Abstract
The apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (ASC) is an essential component of several inflammasomes, multiprotein complexes that regulate caspase-1 activation and inflammation. We report here an interaction between promyelocytic leukemia protein (PML) and ASC. We observed enhanced formation of ASC dimers in PML-deficient macrophages. These macrophages also display enhanced levels of ASC in the cytosol. Furthermore, IL-1β production was markedly enhanced in these macrophages in response to both NLRP3 and AIM2 inflammasome activation and following bone marrow-derived macrophage infection with herpes simplex virus-1 (HSV-1) and Salmonella typhimurium. Collectively, our data indicate that PML limits ASC function, retaining ASC in the nucleus.
Highlights
ASC is the common adaptor of caspase-1 activation in several inflammasomes
IL-1 production was markedly enhanced in these macrophages in response to both NLRP3 and AIM2 inflammasome activation and following bone marrow-derived macrophage infection with herpes simplex virus-1 (HSV-1) and Salmonella typhimurium
PML acts as a scaffold protein for subnuclear structures termed PML nuclear bodies. It is a member of the tripartite motif protein family and contains a characteristic tripartite domain termed RBCC consisting of a RING (R), one or two B-boxes (B), and a PML, promyelocytic leukemia protein; CARD, caspase-activating recruitment domain; BMDM, bone marrow-derived macrophage; m.o.i., multiplicity of infection; co-IP, co-immunoprecipitation
Summary
ASC is the common adaptor of caspase-1 activation in several inflammasomes. Results: A novel interaction between PML and ASC is identified. We report an interaction between ASC and the nuclear body component promyelocytic leukemia protein (PML). PML acts as a scaffold protein for subnuclear structures termed PML nuclear bodies It is a member of the tripartite motif protein family and contains a characteristic tripartite domain termed RBCC consisting of a RING (R), one or two B-boxes (B), and a PML, promyelocytic leukemia protein; CARD, caspase-activating recruitment domain; BMDM, bone marrow-derived macrophage; m.o.i., multiplicity of infection; co-IP, co-immunoprecipitation. The PML transcript undergoes alternative splicing to generate several isoforms, all of which differ solely in their C-terminal region [17, 18] In this regard, a nuclear export sequence is present and retained in the C-terminal portion of PMLI. We have found that PML is a negative regulator of ASC, attenuating inflammasome activation by retaining ASC in the nucleus
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