ZNRF2-mediated CD-M6PR degradation and lysosomal dysfunction aggravate cellular senescence and aging

Area of Science:

• Cell Biology
• Molecular Biology
• Aging Research

Background:

• Lysosomal dysfunction is a key feature of cellular senescence.
• Mechanisms of lysosomal protein transport in senescence are not fully understood.

Purpose of the Study:

• To investigate the role of CD-M6PR in lysosomal dysfunction during cellular senescence.
• To elucidate the molecular mechanisms regulating CD-M6PR levels in senescent cells.

Main Methods:

• Analysis of CD-M6PR levels in senescent fibroblasts, aged mice, and humans.
• Investigating the role of proteasomal degradation and E3 ubiquitin ligases.
• Utilizing structural predictions and experimental validation to identify ZNRF2.
• Examining the link between mTORC1 activation, ZNRF2 expression, and CD-M6PR levels.

Main Results:

• CD-M6PR (cation-dependent mannose-6-phosphate receptor) is significantly reduced in senescent cells and aged tissues, correlating with autolysosomal impairment.
• Reduced CD-M6PR levels are primarily due to accelerated proteasome-mediated degradation.
• ZNRF2, an E3 ubiquitin ligase, was identified as a key mediator of CD-M6PR degradation in senescent cells, with elevated ZNRF2 expression.
• Stress-induced mTORC1 activation increases ZNRF2 expression, leading to decreased CD-M6PR, impaired lysosomal trafficking, and exacerbated senescence.

Conclusions:

• A novel mTORC1-ZNRF2-CD-M6PR signaling axis is identified.
• Aberrant mTORC1 signaling promotes lysosomal dysfunction and cellular senescence via ZNRF2-mediated CD-M6PR degradation.
• This pathway represents a potential therapeutic target for age-related pathologies.