STIL microcephaly mutations interfere with APC/C-mediated degradation and cause centriole amplification

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• STIL is a centriole duplication factor crucial for cell division.
• Mutations in STIL are linked to autosomal recessive primary microcephaly (MCPH).
• Dysregulation of STIL levels can lead to centriole amplification.

Purpose of the Study:

• To elucidate the regulatory mechanisms controlling STIL protein levels.
• To understand how STIL is eliminated at the end of mitosis.
• To investigate the link between STIL stabilization and microcephaly.

Main Methods:

• Fluorescence time-lapse imaging.
• Analysis of STIL protein degradation pathways.
• Identification of key protein domains (e.g., KEN box) involved in degradation.

Main Results:

• STIL undergoes a two-step elimination process at mitosis end.
• Cdk1 mediates STIL translocation from centrosomes to cytoplasm during nuclear envelope breakdown.
• The anaphase-promoting complex/cyclosome (APC/C)-proteasome pathway degrades cytoplasmic STIL via a C-terminal KEN box.
• MCPH-associated STIL mutants lacking the KEN box are resistant to degradation, causing centriole amplification.

Conclusions:

• Cdk1 plays a role in STIL dissociation from centrosomes, impacting cartwheel disassembly.
• STIL stabilization due to mutations leads to centriole amplification.
• Centriole amplification caused by stabilized STIL is proposed as the mechanism underlying microcephaly in MCPH patients.