Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• The 26S proteasome is essential for cellular protein degradation.
• Regulation of the 26S proteasome during physiological processes remains largely unknown.

Purpose of the Study:

• To investigate the regulation of the 26S proteasome through post-translational modifications.
• To identify the kinase responsible for Rpt3 phosphorylation and its functional consequences.

Main Methods:

• CRISPR/Cas9 genome editing
• RNA interference
• Biochemical assays
• Kinome-wide screening

Main Results:

• The 26S proteasome undergoes dynamic phosphorylation at Rpt3-Thr25 during the cell cycle.
• Impaired Rpt3-Thr25 phosphorylation reduces proteasome activity and cell proliferation.
• DYRK2 (dual-specificity tyrosine-regulated kinase 2) was identified as the kinase for Rpt3-Thr25.
• DYRK2-mediated phosphorylation enhances substrate translocation and degradation.
• Loss of Rpt3-Thr25 phosphorylation or DYRK2 inhibits breast cancer cell tumor formation in mice.

Conclusions:

• Proteasome phosphorylation at Rpt3-Thr25 is a key regulatory mechanism.
• DYRK2-Rpt3-Thr25 phosphorylation axis is vital for cell proliferation and tumorigenesis.
• This pathway represents a potential therapeutic target for cancer treatment.