Last update 01 Nov 2024

TMED9

Last update 01 Nov 2024

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 Ltd. (Ireland)

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

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 ; Wibom, Rolf ; Taylor, Robert W. ; Alston, Charlotte L ; Végvári, Ákos ; Taylor, Robert W ; Bruhn, Helene ; Käll, Lukas ; Taylor, Lucie S ; Correia, Sandrina P. ; Lesko, Nicole ; Naess, Karin ; Engvall, Martin ; Lim, Albert Z ; Alston, Charlotte L. ; Moedas, Marco F ; Moedas, Marco F. ; Wredenberg, Anna ; Wedell, Anna ; Correia, Sandrina P ; 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.

20 Sep 2024·Science Advances

Molecular basis of TMED9 oligomerization and entrapment of misfolded protein cargo in the early secretory pathway

Article

Author: Bazua-Valenti, Silvana ; Robinson, Carol V. ; Udeshi, Namrata D. ; Greka, Anna ; Padovano, Valeria ; El-Baba, Tarick ; Grinkevich, Elizabeth ; Wu, Hao ; Pablo, Juan Lorenzo ; Xiao, Le ; Goss, Alissa C. ; Carr, Steven A. ; Pi, Xiong ; Ehrmann, Julian F. ; Carey, Dominique ; Alper, Seth L.

Intracellular accumulation of misfolded proteins causes serious human proteinopathies. The transmembrane emp24 domain 9 (TMED9) cargo receptor promotes a general mechanism of cytotoxicity by entrapping misfolded protein cargos in the early secretory pathway. However, the molecular basis for this TMED9-mediated cargo retention remains elusive. Here, we report cryo–electron microscopy structures of TMED9, which reveal its unexpected self-oligomerization into octamers, dodecamers, and, by extension, even higher-order oligomers. The TMED9 oligomerization is driven by an intrinsic symmetry mismatch between the trimeric coiled coil domain and the tetrameric transmembrane domain. Using frameshifted Mucin 1 as an example of aggregated disease-related protein cargo, we implicate a mode of direct interaction with the TMED9 luminal Golgi-dynamics domain. The structures suggest and we confirm that TMED9 oligomerization favors the recruitment of coat protein I (COPI), but not COPII coatomers, facilitating retrograde transport and explaining the observed cargo entrapment. Our work thus reveals a molecular basis for TMED9-mediated misfolded protein retention in the early secretory pathway.

01 Mar 2024·Molecular Biology of the Cell

The p24-family and COPII subunit SEC24C facilitate the clearance of alpha1-antitrypsin Z from the endoplasmic reticulum to lysosomes

Article

Author: Satpute-Krishnan, Prasanna ; Abishek, Sudhanshu ; Beher, Richa ; Mitra, Debashree ; Roberts, Benjamin S

A subpopulation of the alpha-1-antitrypsin misfolding Z mutant (ATZ) is cleared from the endoplasmic reticulum (ER) via an ER-to-lysosome-associated degradation (ERLAD) pathway. Here, we report that the COPII subunit SEC24C and the p24-family of proteins facilitate the clearance of ATZ via ERLAD. In addition to the previously reported ERLAD components calnexin and FAM134B, we discovered that ATZ coimmunoprecipitates with the p24-family members TMP21 and TMED9. This contrasts with wild type alpha1-antitrypsin, which did not coimmunoprecipitate with FAM134B, calnexin or the p24-family members. Live-cell imaging revealed that ATZ and the p24-family members traffic together from the ER to lysosomes. Using chemical inhibitors to block ER exit or autophagy, we demonstrated that p24-family members and ATZ co-accumulate at SEC24C marked ER-exit sites or in ER-derived compartments, respectively. Furthermore, depletion of SEC24C, TMP21, or TMED9 inhibited lysosomal trafficking of ATZ and resulted in the increase of intracellular ATZ levels. Conversely, overexpression of these p24-family members resulted in the reduction of ATZ levels. Intriguingly, the p24-family members coimmunoprecipitate with ATZ, FAM134B, and SEC24C. Thus, we propose a model in which the p24-family functions in an adaptor complex linking SEC24C with the ERLAD machinery for the clearance of ATZ.

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TMED9

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