TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1

Area of Science:

• Cell Biology
• Molecular Oncology
• Protein Degradation

Background:

• BCL2A1 is an anti-apoptotic protein crucial for chemoresistance in certain cancers.
• BCL2A1's function is regulated by its short half-life, mediated by the ubiquitin-proteasome system.
• The specific enzymes controlling BCL2A1 protein stability remained unidentified.

Purpose of the Study:

• To elucidate the molecular mechanisms regulating BCL2A1 protein stability.
• To identify the E3 ubiquitin ligase responsible for BCL2A1 ubiquitination.
• To investigate the role of TRIM family proteins in BCL2A1 regulation and cancer therapy.

Main Methods:

• Co-immunoprecipitation to assess protein-protein interactions between TRIM28 and BCL2A1.
• Western blotting to detect BCL2A1 ubiquitination and protein levels following TRIM28 knockdown.
• Analysis of TRIM17's effect on BCL2A1 stability and TRIM28 binding.
• Investigation of GSK3's role in BCL2A1 phosphorylation and degradation.
• Assessment of TRIM28 overexpression and TRIM17 knockout effects on BCL2A1 levels and melanoma cell sensitivity to BRAF inhibitors.

Main Results:

• TRIM28 identified as an E3 ubiquitin ligase that binds to BCL2A1 at the mitochondria, promoting its ubiquitination and degradation.
• TRIM17 acts antagonistically to TRIM28, stabilizing BCL2A1 by preventing TRIM28 binding and ubiquitination.
• GSK3 is involved in BCL2A1 phosphorylation, inhibiting its degradation.
• Overexpression of TRIM28 or knockout of TRIM17 decreased BCL2A1 levels and restored sensitivity in melanoma cells treated with BRAF inhibitors.

Conclusions:

• TRIM28 and TRIM17 function as a molecular rheostat, antagonistically regulating BCL2A1 stability.
• This TRIM-mediated regulation of BCL2A1 impacts cell death pathways and chemoresistance.
• Targeting TRIM28 or TRIM17 could represent a novel therapeutic strategy to overcome resistance in BRAF-targeted melanoma therapy.