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A Split-Luciferase-Based Trimer Formation Assay as a High-throughput Screening Platform for Therapeutics in Alport Syndrome.

Abstract：

:Alport syndrome is a hereditary glomerular disease caused by mutation in type IV collagen α3-α5 chains (α3-α5(IV)), which disrupts trimerization, leading to glomerular basement membrane degeneration. Correcting the trimerization of α3/α4/α5 chain is a feasible therapeutic approach, but is hindered by lack of information on the regulation of intracellular α(IV) chain and the absence of high-throughput screening (HTS) platforms to assess α345(IV) trimer formation. Here, we developed sets of split NanoLuc-fusion α345(IV) proteins to monitor α345(IV) trimerization of wild-type and clinically associated mutant α5(IV). The α345(IV) trimer assay, which satisfied the acceptance criteria for HTS, enabled the characterization of intracellular- and secretion-dependent defects of mutant α5(IV). Small interfering RNA-based and chemical screening targeting the ER identified several chemical chaperones that have potential to promote α345(IV) trimer formation. This split luciferase-based trimer formation assay is a functional HTS platform that realizes the feasibility of targeting α345(IV) trimers to treat Alport syndrome.

journal_name

Cell Chem Biol

journal_title

Cell chemical biology

authors

Omachi K,Kamura M,Teramoto K,Kojima H,Yokota T,Kaseda S,Kuwazuru J,Fukuda R,Koyama K,Matsuyama S,Motomura K,Shuto T,Suico MA,Kai H

doi

10.1016/j.chembiol.2018.02.003

subject

Has Abstract

pub_date

2018-05-17 00:00:00

pages

634-643.e4

issue

5

eissn

2451-9456

issn

2451-9448

pii

S2451-9456(18)30043-6

journal_volume

25

pub_type

杂志文章

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