Microtubule-Dependent Regulation of Mitotic Protein Degradation

Abstract

Accurate cell division depends on tightly regulated ubiquitylation events catalyzed by the anaphase-promoting complex. 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.

Spatiotemporal regulation of the anaphase-promoting complex in mitosis

“…Localization of substrates is also important. APC/C substrates that promote mitotic spindle assembly are concentrated on spindle microtubules and hence protected from degradation 80 . Thus substrates are post-translationally modified or differentially localized to regulate timing of their degradation in mitosis.…”

“…In addition the presence of intact microtubules might sequester substrates or promote the transport of the APC/C to favorable subcellular locations (e.g. to chromosomes) for activation 80, 90 .…”

“…Also, an active pool of APC/C-Cdc20 might catalyze the rapid degradation of Cyclin B1 at metaphase upon spindle checkpoint inactivation. Moreover, localization to microtubules protects certain substrates from APC/C mediated degradation 80 while APC/C on centrosomes is anchored there and potentially kept inactive by Emi1–Numa–Dynein-Dynactin complex 94 (Figure 6). An important challenge in the future will be to understand how APC/C localized at specific compartments affect mitotic progression.…”

“…Some APC/C is concentrated at centrosomes where it is bound and potentially inhibited by binding to a protein complex containing Emi1, Numa and Dynein-Dynactin 94 . Spindle assembly factors are localized to microtubules and thereby protected from APC/C-mediated degradation until completion of spindle formation 80 . The spindle checkpoint generates the diffusible mitotic checkpoint complex (MCC) catalyzed at unattached kinetochores to inhibit the soluble cytosolic APC/C (intensity of red color denotes degree of APC/C inhibition, green indicates APC/C activation).…”

Reprint of “Nuclear transport factors: global regulation of mitosis”

“…Rape and colleagues [107,108 ] have discovered thatonce anaphase begins and the Anaphase Promoting Complex (APC/C) is activated by successful chromosome attachmenta higher level of regulation takes over. They found that, unlike cyclin B1 which is ubiquitinated and degraded at the very onset of anaphase, SAFs such as TPX2, HURP, and NuSAP, remain stable through anaphase.…”