TRIM13 regulates caspase-8 ubiquitination, translocation to autophagosomes and activation during ER stress induced...

Area of Science:

• Cellular Biology
• Molecular Biology
• Pathology

Background:

• Endoplasmic reticulum (ER) stress is implicated in diseases like cancer and neurodegeneration.
• Persistent ER stress leads to misfolded protein aggregates, triggering autophagy or caspase-mediated cell death.
• The interplay between autophagy and cell death during ER stress is a critical area of research, with ubiquitination playing a regulatory role.

Purpose of the Study:

• To investigate the role of TRIM13, a RING E3 ubiquitin ligase, in regulating ER stress-induced cell death.
• To elucidate the mechanisms by which TRIM13 influences the crosstalk between ER stress, autophagy, and cell death pathways.

Main Methods:

• Assessing the effect of TRIM13 expression on cellular sensitivity to ER stress.
• Analyzing TRIM13's role in ER stress-induced autophagy and caspase activation.
• Investigating TRIM13-mediated ubiquitination of caspase-8 and its impact on caspase-8 stability and localization.

Main Results:

• TRIM13 expression sensitizes cells to ER stress-induced death.
• TRIM13-induced autophagy is crucial for ER stress-induced caspase activation and subsequent cell death.
• TRIM13 mediates K63-linked poly-ubiquitination of caspase-8, leading to its stabilization and activation during ER stress.
• TRIM13 regulates the translocation of caspase-8 to autophagosomes and their fusion with lysosomes.

Conclusions:

• TRIM13 acts as a novel regulator of ER stress-induced cell death.
• TRIM13 modulates caspase-8 activation and localization through ubiquitination and autophagosome-lysosome fusion pathways.
• This study provides new insights into the molecular mechanisms governing cell fate decisions under ER stress conditions.