Microtubule-dependent regulation of mitotic protein degradation
Ling Song1, Allison Craney1, Michael Rape2
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Abstract:
Accurate cell division depends on tightly regulated ubiquitylation events catalyzed by the anaphase-promoting complex (APC/C). Among its many substrates, the APC/C triggers the degradation of proteins that stabilize the mitotic spindle, and loss or accumulation of such spindle assembly factors can result in aneuploidy and cancer. Although critical for cell division, it has remained poorly understood how the timing of spindle assembly factor degradation is established during mitosis. Here, we report that active spindle assembly factors are protected from APC/C-dependent degradation by microtubules. In contrast, those molecules that are not bound to microtubules are highly susceptible to proteolysis and turned over immediately after APC/C activation. The correct timing of spindle assembly factor degradation, as achieved by this regulatory circuit, is required for accurate spindle structure and function. We propose that the localized stabilization of APC/C substrates provides a mechanism for the selective disposal of cell-cycle regulators that have fulfilled their mitotic roles.
Insights
Microtubules protect spindle assembly factors from degradation by the anaphase-promoting complex (APC/C). This ensures correct cell division timing, preventing aneuploidy and cancer by timely protein turnover.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Accurate cell division relies on regulated ubiquitylation by the anaphase-promoting complex (APC/C).
- APC/C targets spindle assembly factors for degradation; their dysregulation can cause aneuploidy and cancer.
- The precise timing of spindle assembly factor degradation during mitosis is not well understood.
Purpose of the Study:
- To investigate the regulatory mechanisms controlling the timing of spindle assembly factor degradation.
- To elucidate how microtubules influence APC/C-dependent proteolysis of these factors.
Main Methods:
- Studied APC/C activity and substrate degradation in the context of microtubule binding.
- Utilized proteolysis assays to assess turnover rates of spindle assembly factors.
Main Results:
- Microtubules protect active spindle assembly factors from APC/C-mediated degradation.
- Spindle assembly factors not bound to microtubules are rapidly degraded upon APC/C activation.
- This microtubule-dependent regulation ensures timely degradation of proteins after their mitotic function.
Conclusions:
- Microtubule binding acts as a protective mechanism for essential cell division proteins.
- This regulatory circuit is crucial for maintaining accurate spindle structure and function.
- Localized stabilization of APC/C substrates offers a mechanism for selective clearance of proteins post-mitosis.
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