Sensing centrosome amplification: the interface between centriole duplication and autophagy

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Multipolar mitotic spindles with extra centrosomes are observed in cancer cells but poorly understood.
• Centrosome amplification can impose proliferation arrest in cells.

Purpose of the Study:

• To identify pathways that enable cell proliferation despite centrosome amplification.
• To investigate the role of the tumor suppressor ARHGAP15 in overcoming centrosome amplification-induced proliferation arrest.

Main Methods:

• Genome-wide screen to identify pathways involved in proliferation.
• Depletion of ARHGAP15 and assessment of its effects on centrosome number and cell proliferation.
• Investigation of the interaction between ARHGAP15 and autophagy protein ATG16L1.
• Analysis of the ARHGAP15-ARHGEF2-RAC1 pathway.

Main Results:

• Downregulation of Wnt, Hippo, p53, PIDDosome, ciliary biogenesis, or autophagy pathways enables proliferation of cells with PLK4-mediated centrosome amplification.
• Depletion of ARHGAP15 activates autophagy, overcomes centrosome amplification, and enables embryonic fibroblast proliferation.
• Reduction of centrosomes after ARHGAP15 depletion requires ATG16L1 and involves ARHGAP15 association with ATG16L1 when autophagy is inactive.
• ARHGAP15 is opposed by ARHGEF2, which is activated by CEP170 to promote RAC1-GTP generation and autophagy.

Conclusions:

• Specific pathway downregulation allows cells to proliferate despite centrosome amplification.
• ARHGAP15 acts as a tumor suppressor by activating autophagy, reducing centrosome numbers, and promoting proliferation.
• The ARHGAP15-ARHGEF2-CEP170-RAC1 axis plays a crucial role in regulating autophagy and cytoskeletal dynamics.