Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F24%3A10489771" target="_blank" >RIV/00216208:11110/24:10489771 - isvavai.cz</a>

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=JXxldxp8-" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=JXxldxp8-</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1172/JCI180347" target="_blank" >10.1172/JCI180347</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors

Popis výsledku v původním jazyce

The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain-containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.

Název v anglickém jazyce

Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors

Popis výsledku anglicky

The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain-containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30101 - Human genetics

Projekt

<a href="/cs/project/NU21-07-00033" target="_blank" >NU21-07-00033: Identifikace a charakterizace genetických faktorů dědičného tubulointersticiálního onemocnění ledvin II</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Clinical Investigation

ISSN

0021-9738

e-ISSN

1558-8238

Svazek periodika

134

Číslo periodika v rámci svazku

24

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

18

Strana od-do

e180347

Kód UT WoS článku

001380252600003

EID výsledku v databázi Scopus

2-s2.0-85212556855