Center for Molecular Medicine Cologne

Lemberg, Marius | Schiavinato, Alvise | Nüchel, Julian - C 10

Triaging of secretory cargo by interplay of TANGO1 and ERAD-R

Introduction

Protein secretion is an essential process that delivers key components to the extracellular milieu. These components include receptors, cytokines, adhesion molecules, as well as extracellular matrix (ECM) proteins, and mediate key cellular functions, such as signalling, intercellular communication, and adhesion. Cells regulate rapidly and precisely the composition and flux of the extracellular environment and deregulated protein secretion contributes to human disease. A key rate-limiting step for protein secretion is the export of newly synthesized proteins from the Endoplasmic Reticulum (ER). Newly identified mutations in the bulky-cargo ER receptor TANGO1 cause a severe skeletal dysplasia that is associated with defective ECM secretion, as revealed by studies on patient fibroblasts. Our TANGO1 proxiome analysis uncovered for the first time a molecular connection with a regulatory module of the ER-associated degradation pathway (ERAD-R). Therefore, we will further study how the molecular interplay between TANGO1 and ERAD-R finetunes fluctuating degradation/secretion rates of key molecules such as ECM components. We will also study how clinically relevant mutations in the bulky cargo collagen VI are sensed and handled by the quality control machinery tuned by ERAD-R and TANGO1. Our findings will extend our knowledge on the pathogenesis of disorders such as skeletal dysplasia and muscular dystrophies and aim at identifying novel potential targets in the ERAD-R/TANGO1-axis for therapeutic interventions.

Clinical Relevance

Altered structure or remodeling of the extracellular matrix (ECM) disrupts tissue homeostasis. Quality control mechanisms are therefore essential for the proper assembly and secretion of ECM components. In this context we aim to study how the ER-associated degradation (ERAD) pathway, in synergy with the bulky cargo receptor TANGO1, coordinates proper ECM dynamics. We will also study the consequences of patient-derived mutations in TANGO1 and collagen to unveil novel pathomechanisms and to open novel therapeutic avenues.

Prof. Dr. Marius Lemberg CMMC Cologne
Prof. Dr. Marius Lemberg

Deputy Director of the Center for Biochemistry

CMMC - PI - C 10

+49 221 478 77288

Deputy Director of the Center for Biochemistry

Joseph-Stelzmann-Straße 52

50931 Cologne

https://biochemie-med.uni-koeln.de/forschung/arbeitsgruppen/ag-lemberg

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Dr. Alvise Schiavinato CMMC Cologne
Dr. Alvise Schiavinato

Clinic and Polyclinic for Pediatric and Adolescent Medicine

CMMC - Co-PI - C 10

0221 478 6990

Clinic and Polyclinic for Pediatric and Adolescent Medicine

Joseph-Stelzmann-Straße 52

50931 Cologne

https://biochemie-med.uni-koeln.de/

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Dr. Julian Nüchel CMMC Cologne
Dr. Julian Nüchel

Max Planck Institute for Biology of Ageing

CMMC - Co-PI - C 10

Max Planck Institute for Biology of Ageing

Joseph-Stelzmann-Straße 9b

50931 Cologne

https://www.age.mpg.de/

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Publications - Julian Nüchel

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