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

• Published in: The Journal of immunology (1950) 2015-12, Vol.195 (11), p.5415-5420
• Main Authors: Torices, Silvia, Alvarez-Rodríguez, Lorena, Grande, Lara, Varela, Ignacio, Muñoz, Pedro, Pascual, Dora, Balsa, Alejandro, López-Hoyos, Marcos, Martinez-Taboada, Víctor, Fernández-Luna, Jose L
• Format: Article
• Language: English
• Subjects: 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; Male; MCF-7 Cells; 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1501532

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.