IISER MOHALI

DBS Research Spotlight Seminar Series

Speaker:  

Prof. Vivek Malhotra, ICREA Research Professor and Group Leader, CRG (Centre for Genomic Regulation), Barcelona, Spain

About the speaker:  

Prof. Vivek Malhotra is a world leader on protein secretion and cellular compartmentalization.  His laboratory focuses on elucidating the mechanisms by which cells are compartmentalized and ensure the secretion of essential proteins such as collagens, mucins, insulin, hormones, and cytokines of appropriate quality in response to physiological demands. He leads work on investigating how cells synthesize compartments like the Golgi complex and establish exit sites for cargo export at the endoplasmic reticulum. 

You can know more about his research here: 

https://www.crg.eu/en/programmes-groups/malhotra-lab

Abstract:

Receptor-mediated trafficking of secretory cargo at endoplasmic reticulum (ER) via small COPII vesicles is well understood, but the secretion of large cargoes like collagens, mucins, lipoproteins, and antibodies presents challenges due to their size, quantities secreted, and lack of specific receptors. Our discovery of TANGO1, along with cTAGE5 and TANGO1-short, unveils a unique mechanism in which TANGO1 functions to tunnel collagens from ER to the next secretory compartments, bypassing vesicular intermediates. We identified two types of TANGO1 mutations: Class 1 mutations lead to gene deletion and fetal demise, while Class 2 mutations produce a spliced variant that impairs collagen export. Patients with these mutations show short stature, skeletal and dermal abnormalities, and intellectual disability. We also identified two distinct ER exit portals: bulky collagens are confined to about 40% of these sites, while smaller cargoes can exit through any available gate. Our work demonstrates that targeting TANGO1 with membrane-permeant inhibitors controls hypercollagen secretion in dermal cells from scleroderma patients and in a zebrafish wound healing model. These findings present new therapeutic avenues for collagen-related disorders, which will be discussed.