ZW10: an emerging orchestrator of organelle dynamics during the cell division cycle

Abstract

Zeste white 10 (ZW10) was first identified as a centromere/kinetochore protein encoded by the ZW10 gene in Drosophila. ZW10 guides the spindle assembly checkpoint signaling during mitotic chromosome segregation in metazoans. Recent studies have shown that ZW10 is also involved in membrane-bound organelle interactions during interphase and plays a vital role in membrane transport between the endoplasmic reticulum and Golgi apparatus. Despite these findings, the precise molecular mechanisms by which ZW10 regulates interactions between membrane-bound organelles in interphase and the assembly of membraneless organelle kinetochore in mitosis remain elusive. Here, we highlight how ZW10 forms context-dependent protein complexes during the cell cycle. These complexes are essential for mediating membrane trafficking in interphase and ensuring the accurate segregation of chromosomes in mitosis.

Keywords: ZW10; kinetochore; membrane-bound organelle; membraneless organelle; mitosis.

Figure 1

Organization of the kinetochore and its associated proteins. In the central position of the spindle, two chromosomes achieve correct MT attachment, while a chromosome near the left pole fails to establish proper MT attachment. The unattached kinetochore recruits Mps1 kinase, Bub1/BubR1/Bub3, and the RZZ complex. Bub1 and the RZZ complex further recruit Mad1/Mad2, the core protein of the SAC. As a consequence, the unattached kinetochore promotes the assembly of a diffusive ‘waiting anaphase’ signal, the MCC. MCC inhibits APC/C activity and prevents the cell from entering anaphase. Meanwhile, upon establishing correct kinetochore–MT attachment, the dynein–dynactin complex transports RZZ–Mad1/Mad2 along the MTs toward the spindle pole, leading to rapid inactivation of the SAC. Subsequently, APC/C mediates the degradation of securin and cyclin B, ultimately enabling the cell to enter anaphase. KT, kinetochore. Created by BioRender (https://biorender.com).

Figure 2

pH-dependent protein transport between the ER and the Golgi through the ERGIC. Proteins are transported from the ER through the ERGIC and then move into the Golgi apparatus and finally to the plasma membrane. The schematic representation shows different pH-dependent organization mechanisms of anterograde-directed and retrograde-directed recycling proteins in the early secretory pathway. PM, plasma membrane. Created by BioRender (https://biorender.com).

Figure 3

MCSs between the ER and ER-derived organelles. LDs form MCSs with the ER. During LD biogenesis, a lens of neutral lipids accumulates within the ER membrane, eventually forming an LD precursor. Seipin and DGAT2 play crucial roles in the formation of LDs. The ER membrane contains FATP1, which binds with DGAT2 on LDs. The NRZ complex (NAG, RINT1, and ZW10) plays a key role in mediating ER-localized SNAREs (Syntaxin18, Use1, and BNIP1) to form MCSs with Rab18 on LDs (adapted from Wu et al., 2018). Created by BioRender (https://biorender.com).

Figure 4

Organelle dynamics during cell division. Major rearrangements in membrane-bound organelles occur as cells progress in interphase and mitosis. Created by BioRender (https://biorender.com).

Figure 5

Localization of ZW10 during the cell division cycle. HeLa cells were transfected with GFP-ZW10 and mCherry-H2B followed by thymidine synchronization for 16 h. Six hours after release, the cells were stained with ER-Tracker-Blue for 25 min prior to live cell imaging. Merged images show ZW10 (green), the ER (blue), and chromosomes (red). Scale bar, 10 μm.