RNASET2 degrades mRNAs that protect against lipotoxicity.

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• RNASET2 is a lysosomal RNase crucial for cellular responses to lipotoxicity.
• The specific endogenous RNA substrates of RNASET2 that influence lipid-induced cell death remain unidentified.

Purpose of the Study:

• To identify RNASET2 substrates that play a role in lipotoxic stress.
• To elucidate the mechanism by which RNASET2 regulates cellular responses to metabolic stress.

Main Methods:

• RNA sequencing was employed to detect RNA abundance changes following RNASET2 knockdown.
• Actinomycin D assays assessed RNA decay rates, and RNAs were localized to lysosomes.
• The role of the lysosomal transporter SIDT2 in RNA delivery was investigated.
• Loss- and gain-of-function analyses evaluated the impact of identified RNAs on lipotoxic cell death.

Main Results:

• Knockdown of RNASET2 led to increased levels and prolonged decay of UCHL3, PFN2, and PRDX3 mRNAs, resulting in higher protein expression.
• These mRNAs were transported into lysosomes via SIDT2, a process linked to RNautophagy.
• UCHL3 and PFN2, previously not associated with lipotoxicity, demonstrated protective effects against lipid-induced cell death.

Conclusions:

• Specific mRNA substrates of RNASET2 were identified, highlighting a novel function for lysosomes and RNautophagy in metabolic stress response.
• RNautophagy was shown to selectively control the turnover of endogenous RNAs, thereby regulating gene expression.
• This study uncovers a new regulatory pathway involving RNA turnover in cellular adaptation to metabolic challenges.