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Published on: October 9, 2016
A splice variant of ASC regulates IL-1beta release and aggregates differently from intact ASC
Kazuhiko Matsushita1, Michiko Takeoka, Junji Sagara
1Department of Molecular Oncology, Institute on Aging and Adaptation, Graduate School of Medicine, Shinshu University, Negano 390-8621, Japan.
Abstract:
The apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) is involved in apoptosis and innate immunity and is a major adaptor molecule responsible for procaspase-1 activation. ASC mRNA is encoded by three exons: exons 1 and 3 encode a pyrin domain (PYD) and caspase recruit domain (CARD), respectively, and exon 2 encodes a proline and glycine-rich (PGR) domain. Here, we identified a variant ASC protein (vASC) lacking the PGR domain that was smaller than full length ASC (fASC) derived from fully transcribed mRNA and searched for differences in biochemical and biological nature. Both fASC and vASC were found to activate procaspase-1 to a similar degree, but the efficiency of IL-1beta excretion was significantly higher for vASC. There was also a marked structural difference observed in the fibrous aggregates formed by fASC and vASC. These results suggest that although the PGR domain is dispensable for procaspase-1 activation, it plays an important role in the regulation of the molecular structure and activity of ASC.
Insights
A variant ASC protein lacking the proline and glycine-rich (PGR) domain activates procaspase-1 similarly but enhances IL-1beta excretion. The PGR domain regulates ASC
Area of Science:
- Immunology
- Molecular Biology
- Cellular Biology
Background:
- The apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) is a key adaptor in apoptosis and innate immunity.
- ASC mediates procaspase-1 activation, crucial for inflammatory responses.
- ASC mRNA comprises three exons, encoding pyrin domain (PYD), proline and glycine-rich (PGR) domain, and caspase recruit domain (CARD).
Purpose of the Study:
- To investigate the biochemical and biological differences between full-length ASC (fASC) and a variant ASC (vASC) lacking the PGR domain.
- To determine the role of the PGR domain in ASC function, particularly in procaspase-1 activation and IL-1beta secretion.
Main Methods:
- Identification and characterization of a variant ASC protein (vASC) lacking the PGR domain.
- Comparative analysis of procaspase-1 activation by fASC and vASC.
- Assessment of IL-1beta excretion efficiency mediated by fASC and vASC.
- Structural analysis of fibrous aggregates formed by fASC and vASC.
Main Results:
- Both fASC and vASC demonstrated comparable procaspase-1 activation capabilities.
- vASC exhibited significantly higher efficiency in IL-1beta excretion compared to fASC.
- Distinct structural differences were observed in the fibrous aggregates formed by fASC and vASC.
Conclusions:
- The PGR domain is dispensable for procaspase-1 activation by ASC.
- The PGR domain plays a significant role in regulating the molecular structure and biological activity of ASC, particularly IL-1beta secretion.
- Understanding ASC variants can offer insights into modulating inflammatory pathways.
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