A truncated variant of ASCC1, a novel inhibitor of NF-κB, is associated with disease severity in patients with rheumatoid arthritis

Silvia Torices, Lorena Alvarez-Rodŕguez, Lara Grande, Ignacio Varela, Pedro Muñoz, Dora Pascual, Alejandro Balsa, Marcos López-Hoyos, Vctor Martinez-Taboada, Jose L. Fernández-Luna

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-kB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-kB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-kB target genes (TRAIL, TNF-a, cIAP-1, IL8) and blocks activation of a NF-kB-luciferase reporter construct in five different human cell lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78∗) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-kB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-kB and the secretion of TNF-a in response to inflammatory stimuli. We analyzed the clinical impact of p.S78∗variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheumatic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-kB activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA.

Original languageEnglish (US)
Pages (from-to)5415-5420
Number of pages6
JournalJournal of Immunology
Volume195
Issue number11
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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