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

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.

SUBMITTER: Sicking M

PROVIDER: S-EPMC8807872 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Sicking Mark M Živná Martina M Bhadra Pratiti P Barešová Veronika V Tirincsi Andrea A Hadzibeganovic Drazena D Hodaňová Kateřina K Vyleťal Petr P Sovová Jana J Jedličková Ivana I Jung Martin M Bell Thomas T Helms Volkhard V Bleyer Anthony J AJ Kmoch Stanislav S Cavalié Adolfo A Lang Sven S

Life science alliance 20220121 4

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 <i>SEC61A1</i> gene encodes for the pore-forming Sec61α subunit of the Sec61 complex. Despite their ubiquitous expression, the idiopathic <i>SEC61A1</i> missense mutations p.V67G and p.T185A trigger a localized disease pattern diagnosed as autosomal dominant tubulointerstitial kidney disease ...[more]

PMID: 35064074

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Project description:IntroductionThe monocarboxylate transporter 8 (MCT8; SLC16A2) is a specific transporter for thyroid hormones. MCT8 deficiency, formerly known as the Allan-Herndon-Dudley syndrome, is a rare genetic disease that leads to neurological impairments and muscle weakness. Current experimental treatment options rely on thyromimetic agonists that do not depend on MCT8 for cellular uptake. Another approach comes from studies with the chemical chaperone sodium phenylbutyrate (NaPB), which was able to stabilize MCT8 mutants having protein folding defects in vitro. In addition, NaPB is known as a compound that assists with plasma membrane translocation.ObjectiveThe pathogenic MCT8L291R leads to the same severe neurological impairments found for other MCT8-deficient patients but, unexpectedly, lacks alterations in plasma 3,3',5-triiodothyronine (T3) levels. Here we tried to unravel the underlying mechanism of MCT8 deficiency and tested whether the pathogenic MCT8L291R mutant responds to NaPB treatment. Therefore, we overexpressed the mutant in Madin-Darby canine kidney cells in the human choriocarcinoma cell line JEG1 and in COS7 cells of African green monkey origin.ResultsIn our recent study we describe that the MCT8L291R mutation most likely leads to a translocation defect. The pathogenic mutant is not located at the plasma membrane, but shows overlapping expression with a marker protein of the lysosome. Mutation of the corresponding amino acid in murine Mct8 (Mct8L223R) displays a similar effect on cell surface expression and transport function as seen before for MCT8L291R. NaPB was able to correct the translocation defect of MCT8L291R/Mct8L223R and restored protein function by increasing T3 transport activity. Furthermore, we detected enhanced mRNA levels of wild-type and mutant MCT8/Mct8 after NaPB treatment. The increase in mRNA levels could be an explanation for the positive effect on protein expression and function detected for wild-type MCT8.ConclusionNaPB is not only suitable for the treatment of mutations leading to misfolding and protein degradation, but also for a mutant wrongly sorted inside a cell which is otherwise functional.

Dataset Information

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

Publications

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

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