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

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

 Fuente: The Journal of Immunology : Official Journal of the American Association of Immunologists, 2015, 195(11), 5415-20

 Editorial: Williams & Wilkins

 Año de publicación: 2015

 Nº de páginas: 6

 Tipo de publicación: Artículo de Revista

 DOI: 10.4049/jimmunol.1501532

 ISSN: 0022-1767,1550-6606

Autoría

SILVIA TORICES DEL VAL

ALVAREZ RODRÍGUEZ, LORENA

LARA GRANDE GONZALEZ

MUÑOZ, PEDRO

PASCUAL, DORA

BALSA, ALEJANDRO

LÓPEZ HOYOS, MARCOS

JOSE LUIS FERNANDEZ LUNA