A Truncated Variant of ASCC1, a Novel Inhibitor of NF-κB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis.
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.
Servicio de Reumatología, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla, 39011 Santander, Spain; Unidad de Genética, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla, 39011 Santander, Spain;
Silvia
S
Torices
Servicio de Reumatología, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla, 39011 Santander, Spain;
Lorena
L
Alvarez-Rodríguez
Unidad de Genética, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla, 39011 Santander, Spain;
Lara
L
Grande
Servicio de Reumatología, Hospital Universitario La Paz, 08046 Madrid, Spain;
Ignacio
http://orcid.org/0000-0002-0969-506X
I
Varela
Sección de Inmunología, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla, 39011 Santander, Spain;
Pedro
http://orcid.org/0000-0002-1387-2655
P
Muñoz
Instituto de Biomedicina y Biotecnología de Cantabria (Universidad de Cantabria, Consejo Superior de Investigaciones Científicas), 39011 Santander, Spain;
Dora
D
Pascual
Instituto de Biomedicina y Biotecnología de Cantabria (Universidad de Cantabria, Consejo Superior de Investigaciones Científicas), 39011 Santander, Spain;
Alejandro
http://orcid.org/0000-0001-8070-7062
A
Balsa
Gerencia Atención Primaria, Servicio Cántabro de Salud, 39011 Santander, Spain; and.
Marcos
M
López-Hoyos
Servicio de Reumatología, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla, 39011 Santander, Spain; Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain.
Víctor
V
Martinez-Taboada
Unidad de Genética, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla, 39011 Santander, Spain; fluna@humv.es.
Jose L
JL
Fernández-Luna
D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D061986:MCF-7 Cells; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C000605778:ASCC1 protein, human; D018501:Antirheumatic Agents; C508606:CXCL8 protein, human; D002352:Carrier Proteins; D051034:Inhibitor of Apoptosis Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha