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Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin

Publication Type : Journal Article

Thematic Areas : Center for Computational Engineering and Networking (CEN)

Source : Life Science Alliance 5.4 (2022)

Url :

Campus : Coimbatore

School : Computational Engineering and Networking

Center : Center for Computational Engineering and Networking

Verified : No

Year : 2022

Abstract : The human Sec61 complex is a widely distributed and abundant molecular machine. It resides in the membrane of the endoplasmic reticulum to channel two types of cargo: protein substrates and calcium ions. The SEC61A1 gene encodes for the pore-forming Sec61α subunit of the Sec61 complex. Despite their ubiquitous expression, the idiopathic SEC61A1 missense mutations p.V67G and p.T185A trigger a localized disease pattern diagnosed as autosomal dominant tubulointerstitial kidney disease (ADTKD–SEC61A1). Using cellular disease models for ADTKD–SEC61A1, we identified an impaired protein transport of the renal secretory protein renin and a reduced abundance of regulatory calcium transporters, including SERCA2. Treatment with the molecular chaperone phenylbutyrate reversed the defective protein transport of renin and the imbalanced calcium homeostasis. Signal peptide substitution experiments pointed at targeting sequences as the cause for the substrate-specific impairment of protein transport in the presence of the V67G or T185A mutations. Similarly, dominant mutations in the signal peptide of renin also cause ADTKD and point to impaired transport of this renal hormone as important pathogenic feature for ADTKD–SEC61A1 patients as well.

Cite this Research Publication : Mark Sicking, Martina Živná, Pratiti Bhadra, Veronika Barešová,, Andrea Tirincsi, Drazena Hadzibeganovic, Kateřina Hodaňová, Petr Vyleťal, Jana Sovová, Ivana Jedličková Martin Jung; Thomas Bell, Volkhard Helms, Anthony J Bleyer, Stanislav Kmoch, Adolfo Cavalié Sven Lang "Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin", Life Science Alliance 5.4 (2022)

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