A VHL-1;HIF-1/SQRD1/COL-88 axis links extracellular matrix formation with longevity inCaenorhabditis elegans

Abstract

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 nematode Canorhabditis elegans has 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 in vhl-1 mutant worms revealed the sulfide quinone oxidoreductase sqrd-1 to 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 uncharacterised col-88 partially restores lifespan extension and reduces body size of vhl-1/sqrd-1 to vhl-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.