A brand new examine challenges a 60-year-old assumption in regards to the physique’s most important structural constructing block, opening new potentialities for treating fibrosis and most cancers.
For greater than half a century, collagen has been depicted as an extended, inflexible molecular cable, the structural protein that helps give pores and skin, bones, tendons, and organs their energy. However that acquainted picture might seize solely what collagen turns into after it leaves the cell, not the way it really exists whereas being made.
Utilizing high-resolution imaging of dwelling cells, researchers on the Heart for Genomic Regulation (CRG) in Barcelona have now noticed collagen in a strikingly completely different kind: as mushy, liquid-like droplets slightly than stiff rods.
Printed within the Journal of Cell Biology, the examine supplies the primary direct view of essentially the most considerable protein within the human physique in its pure intracellular state. Collagen makes up roughly one-third of the physique’s whole protein mass, but how cells safely bundle and transport such a big structural molecule has remained a longstanding puzzle.
“Inside a cell, collagens are usually not inflexible molecules as one had assumed. They’re actually, very pliable, taking a liquid condensate kind very similar to oil in a drop of water,” explains ICREA Analysis Professor Vivek Malhotra, senior creator of the examine on the CRG in Barcelona.
That liquid-like kind might assist defend cells from their very own structural equipment. Exterior the cell, collagen is supposed to assemble into the inflexible fibers that maintain tissues collectively. If the identical fiber constructing course of occurred contained in the cell, it may very well be lethal.
“That is one other approach by which cells be sure that collagens in all probability by no means grow to be fibrous contained in the cell,” says Malhotra. “As a result of if it have been to grow to be fibrous, it could kill the cell.”
The invention additionally factors to a unique mind-set about how cells export collagen. For many years, many fashions of protein transport have centered on receptors and vesicles, the small membrane sacs that transfer cargo by means of the cell. Work on this transport system within the Eighties and Nineteen Nineties was acknowledged with a Nobel Prize in 2013.
Malhotra and colleagues now suggest a “liquid extrusion” speculation. On this mannequin, collagen strikes from its manufacturing web site to the subsequent compartment of the secretory pathway by means of a bodily course of just like capillary motion. If confirmed, the thought might have an effect on how scientists perceive wound therapeutic, fibrosis, and most cancers.
A sixty-year puzzle in cell biology
Collagen is made inside a mobile compartment referred to as the endoplasmic reticulum (ER). The brand new examine targeted on procollagen 1, a precursor kind that matures into kind 1 collagen. Kind 1 collagen is the physique’s commonest collagen, making up round 90% of whole collagen.
The long-standing puzzle comes from dimension. When purified collagen is seen underneath a microscope, it seems as an extended, inflexible rod that may stretch as much as 400 nanometers. Vesicles, the sacs that usually transport proteins from the place they’re made towards the surface of the cell, are solely about 60 to 90 nanometers throughout.
Ever since collagen’s construction was described greater than half a century in the past, cell biologists have struggled with a fundamental query: how does such a big molecule get out of the cell? The brand new examine means that the reply is partly that collagen has been seen on the improper stage. Contained in the cell, it isn’t but the inflexible rod acquainted from textbook pictures. That construction describes collagen after it has left cells and assembled into tissue-supporting fibers.
Utilizing high-resolution dwell cell imaging of human hepatic stellate cells, the liver cells that make collagen and contribute to scarring in liver fibrosis, the group noticed collagen collect into small droplets. These droplets merged, cut up aside, and exchanged materials with their environment.
These behaviors are hallmarks of a condensate, a concentrated protein compartment that separates from its environment in a approach that resembles oil droplets forming in water.
Based on Soumya Bhattacharyya, first creator of the examine, a lot of cell biology has targeted on condensates within the nucleus and stress granules within the cytosol. “We’re simply starting to grasp condensates contained in the endoplasmic reticulum,” says Bhattacharyya.
The invention: “I had no concept the place it could result in”
The discovering started with microscopy pictures taken in Might 2024 by Dr. Soumya Bhattacharyya, a postdoctoral researcher in Vivek Malhotra’s lab. Bhattacharyya was utilizing liver cells to check what occurs when fibrotic cells enhance collagen manufacturing.
“I had no concept what it could result in. However after we took the samples, what struck me have been these vibrant spherical buildings you possibly can’t miss,” recollects Bhattacharyya.
The lab’s first response was warning. The consequence appeared to problem a deeply held assumption in cell biology.
“I assumed it have to be an artifact,” says Malhotra.
The group then spent months testing whether or not the collagen clusters contained in the endoplasmic reticulum have been merely mobile junk. Cells have a top quality management system for figuring out badly folded proteins, serving to refold them or marking them for destruction. A central participant in that system is a chaperone referred to as BiP.
If the collagen droplets have been piles of misfolded protein, the researchers anticipated to search out excessive ranges of BiP. As a substitute, the droplets contained helper proteins, together with chaperones that particularly acknowledge correctly folded collagen.
The position of TANGO1
The examine additionally sheds gentle on TANGO1, a protein found by the Malhotra lab about twenty years in the past and identified to be important for collagen export. When the researchers depleted TANGO1, collagen droplets nonetheless fashioned. Nonetheless, they now not sat on the ER exit websites the place cargo leaves the compartment, and collagen secretion fell.
That consequence suggests TANGO1 acts much less like a traditional cargo receptor and extra like a mooring level that holds the collagen droplet on the export web site. The authors suggest that collagen might then go away the cell by means of wetting, a bodily course of by which the liquid droplet attaches to and flows by means of the exit web site.
Malhotra provides two potential bodily mechanisms for this switch. “Think about you have got a rubber ball with a nozzle, stuffed with liquid. You squeeze it, you power the liquid to come back out of this little orifice. Is that the mechanism? Or is the liquid rising by capillary forces, identical to vitamins move up towards gravity in crops by capillary motion?”
The liquid extrusion mannequin stays a speculation. The group is already planning the subsequent experiments to immediately visualize the export mechanism. The researchers additionally plan to work with exterior companions to develop a mouse mannequin and check whether or not the identical course of happens in dwelling tissue.
Implications for fibrosis and most cancers
If confirmed, the mannequin might matter for ailments by which cells secrete an excessive amount of collagen. These embrace liver, lung, and pores and skin fibrosis, in addition to cancers that use a dense collagen-rich matrix to defend themselves from chemotherapy and the immune system.
“One of many main issues in most cancers is that the cells secrete so many collagens and different proteins out into the extracellular matrix that they conceal in a shell made of those elements and grow to be chemo- and immuno-refractory, which means they don’t seem to be seen by the chemical therapeutics or by the immune system,” Malhotra says.
“Individuals are looking for methods to interrupt this tissue cement and our examine might assist inform these methods,” he provides.
The proposed mannequin factors to potential new methods. One could be to degrade TANGO1, stopping collagen cargo from being captured on the exit web site. One other could be to dissolve the condensate itself, stopping the cargo from being organized earlier than export. Each concepts stay exploratory, however they provide new methods to consider controlling the physique’s most considerable structural protein.
Reference: “Procollagen 1 assembles into phase-separated condensates within the endoplasmic reticulum” by Soumya Bhattacharyya, Jose Wojnicki, Nathalie Brouwers, and Vivek Malhotra, 11 June 2026, Journal of Cell Biology.
DOI: 10.1083/jcb.202603129
Funding: Ministerio de Ciencia, Innovación y Universidades (España), Generalitat de Catalunya, European Analysis Council
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