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

Author:

Sicking Mark1,Živná Martina2,Bhadra Pratiti3,Barešová Veronika2,Tirincsi Andrea1ORCID,Hadzibeganovic Drazena1,Hodaňová Kateřina2,Vyleťal Petr2,Sovová Jana2,Jedličková Ivana2,Jung Martin1ORCID,Bell Thomas4,Helms Volkhard3ORCID,Bleyer Anthony J25,Kmoch Stanislav2,Cavalié Adolfo6,Lang Sven1ORCID

Affiliation:

1. Department of Medical Biochemistry and Molecular Biology, Saarland University, Homburg, Germany

2. Research Unit for Rare Diseases, Department of Pediatrics and Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czech Republic

3. Center for Bioinformatics, Saarland University, Saarbrücken, Germany

4. Department of Chemistry, University of Nevada, Reno, NV, USA

5. Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA

6. Experimental and Clinical Pharmacology and Toxicology, Pre-clinical Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany

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.

Funder

Deutsche Forschungsgemeinschaft

Ministry of Health of the Czech Republic

Charles University

Saarland University Medical Center

Publisher

Life Science Alliance, LLC

Subject

Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology

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