A VHL-1;HIF-1/SQRD1/COL-88 axis links extracellular matrix formation with longevity inCaenorhabditis elegans
Authors: Salgueiro Willian , Esmaillie Reza , Bohl Katrin , Statzer Cyril , Bharill Puneet , Bargfrede Sebastian , Chokkalingam Manopriya , Neutzer Maike , Ignarski Michael , Benzing Thomas , Beyer Andreas , Schermer Bernhard , Ewald Collin Y. , Fabretti Francesca , Müller Roman-Ulrich 
Published: February 2024

The extracellular matrix (ECM) is a pivotal three-dimensional network crucial for tissue organization, cellular communication, and fundamental cellular processes, where collagens are the major chemical entity in amount. ECM deregulation is directly involved with several pathologies, such as tumour growth and invasiveness, atherosclerosis, and diabetic nephropathy. Mutations in the von Hippel-Lindau tumour suppressor (pVHL) cause VHL syndrome, a multi-tumour syndrome commonly associated with clear cell renal carcinoma (ccRCC). Loss of pVHL is associated with the activation of hypoxia-inducible factor (HIF) signaling. Mutation of VHL-1 in the nematodeCanorhabditis eleganshas been shown to increase lifespan and stress resistance. Interestingly, considering recent findings on the involvement of collagens in the regulation of lifespan, we also observed these animals to show defects in body morphology in a HIF-1 dependent manner. Based on this finding, we established a link between HIF-1 activation upon loss of VHL-1 and ECM defects associated with alterations in collagen expression. An RNAi screen examining genes upregulated invhl-1mutant worms revealed the sulfide quinone oxidoreductasesqrd-1to mediate the change in body morphology. SQRD-1 is essential to the HIF-1 dependent increase in several collagen genes. One of these genes,col-88, partly mediates both the impact of loss of VHL-1 on lifespan extension and body length. The downregulation of the uncharacterisedcol-88partially restores lifespan extension and reduces body size ofvhl-1/sqrd-1tovhl-1(ok161)single mutant. This study contributes to the increasing body of evidence linking lifespan extension and the ECM and now implicates this axis in hypoxia-signaling. These findings are of special interest considering the role of ECM integrity in tumour growth and metastasis.

Author Summary

The extracellular matrix and its composing collagens are associated with a wide number of diseases, including cancer. The von Hippel-Lindau tumour suppressor (pVHL) is known to work by regulating the Hypoxia Inducible Factor (HIF) to help the organism to adapt to lack of oxygen. Mutations in pVHL are associated with clear cell renal carcinoma (ccRCC). Interestingly, a small number of studies have shown that pVHL can be directly associated with collagens, a function that is independent of its classical role regulating HIF. However, there is no further knowledge about which role the hypoxia pathway has when it comes to extracellular matrix formation and function, what would be useful since the invasiveness of cancers, such as ccRCC, are directly connected to their matrix/collagen composition. Here we observed that the model organismC. eleganshas drastically different collagen composition and body size upon a mutation on itsvhl-1gene. Furthermore, a protein previously only known to be involved in sulfide metabolism, SQRD-1, connects body size and lifespan in this animal model, revealing a surprising link between the hypoxia pathway and sulfur metabolism to control lifespan. Further studies could target sulfur metabolism in ccRCC to modulate collagen production and tumour invasiveness.