MIG-6/papilin is a global regulator of the extracellular matrix and affects TGF-β signaling

The extracellular matrix (ECM) regulates [CB1] cell behavior through structural and biochemicalsignals. In addition to providing mechanical support, it regulates morphogen presentation andligand availability, ensuring appropriate activation of signaling pathways. We previouslyidentified the conserved ECM protein MIG 6S/papilin as a critical regulator of collagen IVhomeostasis. The loss of mig-6 function leads to fibrotic collagen IV accumulation and impactscollagen IV-crosslinking enzyme peroxidasin, as well as affecting laminin and fibulin. Toinvestigate the molecular underpinnings of these ECM phenotypes, we systematicallyinterrogated multiple ECM components. We used endogenously and multicopy taggedreporters, as well as genetic perturbations, to focus on the presence of diverse ECMcomponents in mig-6 mutants' collagen IV fibrotic structures and on their role in the ECM. Ourresults show that loss of mig-6 deregulates the levels/localization of numerous ECMcomponents, including collagen XV/XVIII, hemicentin, perlecan, fibrilin, and tissues inhibitors ofmetalloproteinases. Importantly, only a subset of these colocalize and influence mig-6 mutants'fibrotic collagen IV. Moreover, we previously showed that TGF-β signaling is less active in mig-6mutants, but the origin of this effect remained unclear. We therefore generated a fluorescentreporter to visualize extracellular TGF-β ligand DBL 1 and find that DBL-1 accumulates withinfibrotic structures in mig-6 mutants. This work contributes to understanding general principlesof extracellular matrix remodeling and identifying factors that modulate signaling. This isexpected to shed light onto the pathogenic mechanisms underlying orphan diseases such asthe Loeys Dietz syndrome (1:50,000), which is associated with mutations in TGF-β components.