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Expression of a PYCARD/ASC variant lacking exon 2 in Japanese patients with palindromic rheumatism increases
Yumi Suganuma1, Hayate Tanaka1, Aya Kawase1
1Division of Medical Biophysics, Department of Biophysics, Graduate School of Health Sciences, Kobe University, Kobe, Japan.
Background:
Palindromic rheumatism (PR) is a rare periodic arthritis characterized by relapsing short episodes of arthritis. Although the pathogenesis of PR is still unclear, the clinical condition is similar to that of autoinflammatory diseases caused by dysregulation of inflammasome-related genes.
Objective:
We analyzed the inflammasome adapter PYD and CARD domain-containing protein/apoptosis-associated speck-like protein containing a CARD (PYCARD/ASC) in Japanese patients with PR.
Methods:
Serum interleukin (IL)-1β concentrations in three Japanese patients with PR were measured. We also cloned PYCARD/ASC cDNA variants and expressed them in THP-1 cells to determine their effects on inflammasome activity following stimulation with phorbol 12-myristate 13-acetate and monosodium urate. Lysates of recombinant THP-1 cells were subjected to co-immunoprecipitation assays.
Results:
Serum IL-1β concentrations were significantly elevated in patients with PR, and a splice variant of PYCARD/ ASC mRNA lacking exon 2 (Δexon2) was dominantly expressed compared with that in controls. Moreover, IL-1β secretion was significantly increased in THP-1 cells expressing Δexon2PYCARD/ASC compared with that in cells expressing the wild-type protein. The amount of NLRP3 bound to Δexon2PYCARD/ASC was increased after stimulation, whereas that bound to the wild-type protein was decreased. There were no differences in caspase-1 binding.
Conclusions:
Δexon2 PYCARD/ASC was associated with the pathogenesis of PR.
Insights
A novel splice variant of PYCARD/ASC, lacking exon 2 (Δexon2), is linked to palindromic rheumatism (PR) pathogenesis. This variant elevates IL-1β secretion and alters NLRP3 inflammasome interactions, suggesting a role in this rare autoinflammatory disease.
Area of Science:
- Immunology
- Genetics
- Rheumatology
Background:
- Palindromic rheumatism (PR) is a rare autoinflammatory disease with unclear pathogenesis.
- PR shares clinical similarities with autoinflammatory conditions linked to inflammasome gene dysregulation.
Purpose of the Study:
- To investigate the role of the inflammasome adapter PYD and CARD domain-containing protein/apoptosis-associated speck-like protein containing a CARD (PYCARD/ASC) in Japanese patients with PR.
- To analyze the functional impact of PYCARD/ASC variants on inflammasome activity.
Main Methods:
- Measured serum IL-1β levels in PR patients.
- Cloned and expressed PYCARD/ASC variants in THP-1 cells.
- Assessed inflammasome activity and protein interactions via co-immunoprecipitation.
Main Results:
- Serum IL-1β was elevated in PR patients.
- A PYCARD/ASC splice variant lacking exon 2 (Δexon2) was predominantly expressed.
- Δexon2 PYCARD/ASC enhanced IL-1β secretion and increased NLRP3 binding in response to stimulation.
Conclusions:
- The Δexon2 PYCARD/ASC variant is associated with the pathogenesis of palindromic rheumatism.
- This finding implicates inflammasome dysregulation in PR development.
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