A Truncated Variant of ASCC1, a Novel Inhibitor of NF-κB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis

J Immunol. 2015 Dec 1;195(11):5415-20. doi: 10.4049/jimmunol.1501532. Epub 2015 Oct 26.


Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-κB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-κB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-κB target genes (TRAIL, TNF-α, cIAP-1, IL8) and blocks activation of a NF-κB-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-κB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-κB and the secretion of TNF-α 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-κB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antirheumatic Agents / therapeutic use
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / pathology*
  • Base Sequence
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Line, Tumor
  • Enzyme Activation
  • Female
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Inhibitor of Apoptosis Proteins / biosynthesis
  • Interleukin-8 / biosynthesis
  • MCF-7 Cells
  • Male
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Sequence Analysis, DNA
  • Signal Transduction / genetics
  • TNF-Related Apoptosis-Inducing Ligand / biosynthesis
  • Transcriptional Activation / genetics*
  • Tumor Necrosis Factor-alpha / biosynthesis


  • ASCC1 protein, human
  • Antirheumatic Agents
  • CXCL8 protein, human
  • Carrier Proteins
  • Inhibitor of Apoptosis Proteins
  • Interleukin-8
  • NF-kappa B
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha