Unveiling the Role of PSMB10 Gene Splice Variant in Dominantly Inherited Auto- inflammatory Disease: Insights into Autophagy Interaction and Clinical Im

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Savsar B., Tonbul Z., Onat U. İ., Sever E., Uğurlu S., Öz Arslan D., ...Daha Fazla

Molbiyokon24, İzmir, Türkiye, 12 - 14 Eylül 2024, ss.241, (Özet Bildiri)

  • Yayın Türü: Bildiri / Özet Bildiri
  • Basıldığı Şehir: İzmir
  • Basıldığı Ülke: Türkiye
  • Sayfa Sayıları: ss.241
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Evet

Özet

 AIM: The autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) are two major proteolytic processes responsible for the degradation of misfolded and damaged proteins. In this study, we investigated autophagic flux in the peripheral blood mononuclear cells (PBMCs) of a family suffering from undiagnosed systemic autoinflammatory disease (SAID) with a variant of unknown significance (VUS) in the PSMB10 (rs201451622, NM_002801:exon1:c.56+1G>A) gene. The PSMB10 gene encodes the beta 2 subunit of the 20S proteasome, and this variant could lead to a splicing error, based on splicing in silico analysis. Our objective was to assess both gene and protein expression related to autophagy biomarkers in PBMC samples from affected and healthy individuals.

METHODS: PBMCs were isolated from blood samples collected from affected and healthy individuals. PBMCs were cultured in RPMI 1640 medium and exposed to Bafilomycin A1 (100 nM) to inhibit the autophagy flux. LC3B expression level was determined using Western blotting. ULK1, and ATG14 expression levels were evaluated. Statistical significance of differences was calculated by one-way ANOVA.

RESULTS: Higher autophagic flux observed in affected family members, carrying PSMB10 variant, compared to unaffected members. In P1, P2, and P4 patients, a 0.2-fold in ULK1 gene expression and a 0.1-fold in ATG14 gene expression decrease were observed compared to healthy controls. Similarly, 0.3 and 0.4 fold change (LC3BII/LC3BI) decrease were observed in P2-P3-P4 compared to controls. Increased LC3B-II expression in patients confirmed that high autophagic flux was suppressed.

CONCLUSION: Patients carrying the PSMB10 variant demonstrated higher autophagic flux, indicating a potential role of this variant in SAIDs. This research enhances our understanding of the autophagy pathway and provides preliminary data for treatment process of the patients. Future studies will examine the localization and properties of autophagosomes and determine the relationship between abnormal autophagy and the novel PSMB10 variant.

Keywords: PSMB10, Autophagy, PBMC, SAID