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Last update 08 May 2025

TMED9

Last update 08 May 2025

Basic Info

Synonyms

Glycoprotein 25L2, GMP25, GP25L2

+ [8]

Introduction

Appears to be involved in vesicular protein trafficking, mainly in the early secretory pathway. In COPI vesicle-mediated retrograde transport involved in the coatomer recruitment to membranes of the early secretory pathway. Increases coatomer-dependent activity of ARFGAP2. Thought to play a crucial role in the specific retention of p24 complexes in cis-Golgi membranes; specifically contributes to the coupled localization of TMED2 and TMED10 in the cis-Golgi network. May be involved in organization of intracellular membranes, such as of the ER-Golgi intermediate compartment and the Golgi apparatus. Involved in ER localization of PTPN2 isoform PTPB.

Drugs associated with TMED9

AGN 192403

Target

I1 receptor x TMED9

Mechanism

I1 receptor modulators [+1]

Active Org.

Allergan plc

Originator Org.

Allergan UC

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

BRD-4780

Target

TMED9

Mechanism

TMED9 modulators

Active Org.-

Originator Org.

The Broad Institute, Inc.

Active Indication-

Inactive Indication

Medullary Cystic Kidney Disease

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TMED9

100 Translational Medicine associated with TMED9

0 Patents (Medical) associated with TMED9

Literatures (Medical) associated with TMED9

16 Dec 2024·Journal of Clinical Investigation

Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors

Article

Author: Weins, Astrid ; Kmoch, Stanislav ; Mutig, Kerim ; Lin, John ; Živná, Martina ; Keller, Keith H ; Bleich, Markus ; Himmerkus, Nina ; Zavras, Jason ; Kidd, Kendrah ; Yoo, Hyery ; Brown, Matthew R ; Carr, Steven A ; Quintanova, Catarina ; Sidhom, Eriene-Heidi ; Dvela-Levitt, Moran ; Bazua-Valenti, Silvana ; Udeshi, Namrata ; Halbritter, Jan ; Alper, Seth L ; Vaca Jacome, Alvaro S ; Racette, Matthew ; Greka, Anna ; Bleyer, Anthony J ; Riedl Khursigara, Magdalena ; Shaw, Jillian L ; Grinkevich, Elizabeth ; Papanastasiou, Malvina ; Pablo, Juan Lorenzo B ; Bachmann, Sebastian ; Goss, Alissa C ; Demirci, Hasan ; Kost-Alimova, Maria ; Sewerin, Sebastian

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.

22 Oct 2024·JCI Insight

Quantitative proteomics of patient fibroblasts reveal biomarkers and diagnostic signatures of mitochondrial disease

Article

Author: Lim, Albert Z. ; Kazior, Zuzanna ; Freyer, Christoph ; Taylor, Robert W. ; Wibom, Rolf ; Alston, Charlotte L ; Taylor, Robert W ; Végvári, Ákos ; Taylor, Lucie S ; Käll, Lukas ; Bruhn, Helene ; Correia, Sandrina P. ; Lesko, Nicole ; Naess, Karin ; Engvall, Martin ; Lim, Albert Z ; Alston, Charlotte L. ; Moedas, Marco F ; Moedas, Marco F. ; Wredenberg, Anna ; Correia, Sandrina P ; Wedell, Anna ; McFarland, Robert ; Taylor, Lucie S. ; Trost, Matthias ; Rumyantseva, Anastasia

BACKGROUNDMitochondrial diseases belong to the group of inborn errors of metabolism (IEM), with a prevalence of 1 in 2,000-5,000 individuals. They are the most common form of IEM, but, despite advances in next-generation sequencing technologies, almost half of the patients are left genetically undiagnosed.METHODSWe investigated a cohort of 61 patients with defined mitochondrial disease to improve diagnostics, identify biomarkers, and correlate metabolic pathways to specific disease groups. Clinical presentations were structured using human phenotype ontology terms, and mass spectrometry-based proteomics was performed on primary fibroblasts. Additionally, we integrated 6 patients carrying variants of uncertain significance (VUS) to test proteomics as a diagnostic expansion.RESULTSProteomic profiles from patient samples could be classified according to their biochemical and genetic characteristics, with the expression of 5 proteins (GPX4, MORF4L1, MOXD1, MSRA, and TMED9) correlating with the disease cohort, thus acting as putative biomarkers. Pathway analysis showed a deregulation of inflammatory and mitochondrial stress responses. This included the upregulation of glycosphingolipid metabolism and mitochondrial protein import, as well as the downregulation of arachidonic acid metabolism. Furthermore, we could assign pathogenicity to a VUS in MRPS23 by demonstrating the loss of associated mitochondrial ribosome subunits.CONCLUSIONWe established mass spectrometry-based proteomics on patient fibroblasts as a viable and versatile tool for diagnosing patients with mitochondrial disease.FUNDINGThe NovoNordisk Foundation, Knut and Alice Wallenberg Foundation, Wellcome Centre for Mitochondrial Research, UK Medical Research Council, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children.

01 Oct 2024·Biochemical Genetics

Assessment of Genomic Diversity and Selective Pressures in Crossbred Dairy Cattle of Pakistan

Article

Author: Nisa, Fakhar Un ; Mrode, Raphael ; Ilyas, Iram ; Amin, Imran ; Naqvi, Rubab Zahra ; Mukhtar, Zahid ; Arshad, Fazeela ; Asif, Muhammad ; Mansoor, Shahid

Improving the low productivity levels of native cattle breeds in smallholder farming systems is a pressing concern in Pakistan. Crossbreeding high milk-yielding holstein friesian (HF) breed with the adaptability and heat tolerance of Sahiwal cattle has resulted in offspring that are well-suited to local conditions and exhibit improved milk yield. The exploration of how desirable traits in crossbred dairy cattle are selected has not yet been investigated. This study aims to provide the first overview of the selective pressures on the genome of crossbred dairy cattle in Pakistan. A total of eighty-one crossbred, thirty-two HF and twenty-four Sahiwal cattle were genotyped, and additional SNP genotype data for HF and Sahiwal were collected from a public database to equate the sample size in each group. Within-breed selection signatures in crossbreds were investigated using the integrated haplotype score. Crossbreds were also compared to each of their parental breeds to discover between-population signatures of selection using two approaches: cross-population extended haplotype homozygosity and fixation index. We identified several overlapping genes associated with production, immunity, and adaptation traits, including U6, TMEM41B, B4GALT7, 5S_rRNA, RBM27, POU4F3, NSD1, PRELID1, RGS14, SLC34A1, TMED9, B4GALT7, OR2AK3, OR2T16, OR2T60, OR2L3, and CTNNA1. Our results suggest that regions responsible for milk traits have generally experienced stronger selective pressure than others.

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TMED9

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