Autophagy deficiency activates rDNA transcription

Area of Science:

• Cell Biology
• Molecular Biology
• Autophagy Research

Background:

• Macroautophagy/autophagy is a lysosome-dependent pathway crucial for regulating cell metabolism through the degradation of intracellular components.
• The precise role of autophagy in RNA metabolism, particularly in ribosomal RNA (rRNA) synthesis, remains incompletely understood.

Purpose of the Study:

• To investigate the regulatory role of autophagy in ribosomal RNA (rRNA) synthesis and its connection to RNA metabolism.
• To elucidate the molecular mechanisms by which autophagy deficiency impacts rRNA production and cellular processes.

Main Methods:

• Analysis of 47S precursor rRNA levels in autophagy-deficient cells.
• Investigation of SQSTM1/p62 accumulation and its effect on MTORC1 signaling.
• Assessment of RNA polymerase I pre-initiation complex assembly at ribosomal DNA (rDNA) promoters.
• Evaluation of protein synthesis, cell growth, and proliferation in the context of autophagy deficiency.

Main Results:

• Autophagy-deficient cells exhibit significantly higher levels of 47S precursor rRNA due to SQSTM1/p62 accumulation.
• SQSTM1 accumulation activates MTORC1 signaling, promoting RNA polymerase I pre-initiation complex assembly and increasing 47S rRNA transcription.
• Autophagy deficiency enhances protein synthesis, cell growth, and proliferation, dependent on SQSTM1 accumulation.

Conclusions:

• Autophagy deficiency impacts RNA metabolism by activating rDNA transcription, mediated by SQSTM1/p62 and MTORC1 signaling.
• These findings reveal novel mechanisms for metabolic reprogramming in autophagy-related diseases, including various cancers.
• Autophagy plays a critical role in maintaining cellular homeostasis by regulating rRNA synthesis and preventing uncontrolled cell growth.