Metabolic regulation of RNA decay

Although excess lipid accumulation in non-adipose tissues is initially well tolerated, this metabolic excess ultimately causes cell dysfunction and cell death that is linked to the pathogenesis of complications of diabetes and obesity. Through a genetic screen, we discovered that RNASET2, a T2 endoribonuclease, is a critical mediator of oxidative stress damage and cell death in response to lipotoxicity. Catalytic activity of this lysosomal T2 endoribonuclease is required for lipotoxic cell death, but to date, no endogenous RNA substrates have been identified.

What are the endogenous RNASET2 substrates that regulate metabolic stress? We are using RNA sequencing based approaches to learn about the role of this enzyme in metabolic stress responses.

How do RNASET2 substrates reach this organelle? We are investigating the contribution of autophagy to the degradation of RNASET2 substrates and the response to metabolic stress.