Evidence map›Paper›PMID 39680459›Full record

ArticleThe Journal of clinical investigation2024

Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors.

Silvana Bazua-Valenti, Matthew R Brown, Jason Zavras, Magdalena Riedl Khursigara, Elizabeth Grinkevich, Eriene-Heidi Sidhom, Keith H Keller, Matthew Racette, Moran Dvela-Levitt, Catarina Quintanova and 24 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

15 citing papers in PubMed.

  1. Review
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  11. Review
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  13. Uromodulin modulates mitochondria and kidney tubule resilience.The Journal of clinical investigation · 2025
    Article
  14. Article
  15. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

34 authors.

Silvana Bazua-ValentiThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Matthew R BrownThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Jason ZavrasThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Magdalena Riedl KhursigaraThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Elizabeth GrinkevichThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Eriene-Heidi SidhomThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Keith H KellerThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Matthew RacetteThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Moran Dvela-LevittThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Catarina QuintanovaInstitute of Physiology, Christian - Albrechts - Universität, Kiel, Germany.
Hasan DemirciInstitute of Translational Physiology and.
Sebastian SewerinThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Alissa C GossThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
John LinThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Hyery YooThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Alvaro S Vaca JacomeProteomics Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Malvina PapanastasiouProteomics Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Namrata UdeshiProteomics Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Steven A CarrProteomics Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Nina HimmerkusInstitute of Physiology, Christian - Albrechts - Universität, Kiel, Germany.
Markus BleichInstitute of Physiology, Christian - Albrechts - Universität, Kiel, Germany.
Kerim MutigInstitute of Translational Physiology and.
Sebastian BachmannInstitute of Translational Physiology and.
Jan HalbritterDepartment of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin, Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Stanislav KmochResearch Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Martina ŽivnáResearch Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Kendrah KiddSection on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina, USA.
Anthony J BleyerSection on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina, USA.
Astrid WeinsDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Seth L AlperThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Jillian L ShawThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Maria Kost-AlimovaThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Juan Lorenzo B PabloThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
Anna GrekaThe Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.

Funding

Medical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7M
Opera Phenix high-throughput microplate confocal imager for high-content screeningS10OD026839 · OD · BROAD INSTITUTE, INC. · PI WAGNER, BRIDGET K · 2019 to 2019
$1.0M
NBCe1-mediated Regulation of HCO3- is a Novel Mechanism Underlying Metabolic Reprogramming and CystogenesisK00DK123834 · NIDDK · BROAD INSTITUTE, INC. · PI BROWN, MATTHEW · 2022 to 2025
$369k
NIDDK NIH HHS K00 DK123834NIGMS NIH HHS T32 GM144273NIH HHS S10 OD026839
6 · The paper itself

Abstract

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.

Indexed as

Protein TransportUromodulinAnimalsHumansMembrane GlycoproteinsMiceMutationMembrane GlycoproteinsUMOD protein, humanUmod protein, mouseUromodulinGenetic diseasesNephrologyProtein misfoldingProtein traffic

Identifiers

PMID39680459
PMCPMC11645142

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.