Mitosis controls the Golgi and the Golgi controls mitosis
Introduction
The Golgi ribbon is a continuous membranous system that is localized to the perinuclear area, and it has an essential role in secretory trafficking, lipid biosynthesis, protein modifications and the sorting and transport of proteins [1]. The ribbon is composed of individual stacks of flattened cisternae that are laterally connected with adjacent stacks by membranous tubular bridges, which are known as the ‘non-compact zones’ (Figure 1) [2]. Many factors contribute to the formation and maintenance of the peculiar structure of the Golgi complex, including Golgi ‘matrix’ proteins (a complex network of coiled-coil golgins and GTPases, reviewed in reference [3], see also legend to Figure 1), specialized cytoskeleton-based motors (that determine the Golgi perinuclear location [3, 4], see also reference [5••]), regulatory kinases [6••] and a constant membrane input from the endoplasmic reticulum (ER) [7].One intriguing aspect of the physiology of the Golgi membranes is the mechanism of their mitotic inheritance. This involves the progressive and reversible disassembly of the ribbon into dispersed elements to allow the correct partitioning of the Golgi membranes between daughter cells [8, 9, 10]. This process of Golgi partitioning has attracted interest also because of the general mechanistic information that can be obtained from the elucidation of the molecules and mechanisms regulating the mitotic disassembly/reassembly of the Golgi complex. Indeed, a number of molecular players have been characterized through in vitro assays of Golgi mitotic fragmentation and reassembly. These include numerous kinases, such as Cdc2, RAF/MEK1/ERK1c, Plk1 and Plk3 [9, 11, 12, 13, 14, 15•], the fissioning protein C-terminal-binding protein 1, short form/brefeldin-A-dependent ADP-ribosylation substrate (CtBP1-S/BARS) [16], several golgins, including GM130, Golgi complex associated protein of 65 kDa (GRASP-65) and Golgin 84 [17, 18, 19] and protein complexes involved in supporting membrane fusion [20, 21]. The cytoskeleton may also have a role in Golgi reorganization during mitosis, since microtubules appear to guide the movement of Golgi fragments from prophase till metaphase [22] and to be required for full disruption of Golgi clusters during metaphase [23].
Another unexpected and striking outcome of studies into Golgi partitioning is that Golgi fragmentation has been shown to be required for entry into mitosis, suggesting the existence of a novel ‘Golgi mitotic checkpoint’ dedicated to linking the state of assembly of the Golgi complex with the process of entry into mitosis [16, 18, 24•]. The main evidence for this checkpoint is that the inhibition of Golgi fragmentation via a functional block of the proteins involved in this process (GRASP-65 and CtBP1-S/BARS) results in the arrest of the cell cycle at the G2 stage [16, 18, 25•]. Also, inhibition and/or depletion of the MAP kinase components controlling Golgi fragmentation, such as RAF1, mitogen activated protein kinase kinase 1 (MEK1) and extracellular signal-regulated kinase 1c (ERK1c), results in a significant delay of G2/M transition [6••, 9, 15•]. Here, we review recent advances in the mechanisms of Golgi fragmentation in mammalian cells and their implication for the regulation of cell cycle transitions.
Section snippets
The severing of the ribbon in G2 is the Golgi fragmentation step essential to progress into mitosis
Remarkably, and seemingly at odds with the concept of a G2/M Golgi checkpoint, the first evident sign of mitotic Golgi fragmentation that was reported was the Golgi breakdown into membrane ‘blobs’ that initiated during prophase, that is paradoxically, after G2 [8]. Now, two recent independent investigations focused on the role of CtBP1-S/BARS (from now on BARS) and MEK1 in Golgi partition have resolved this inconsistency and elucidated the Golgi fragmentation step essential for mitotic entry,
Proteins and mechanisms involved in the severing of the Golgi ribbon in G2
A crucial aspect that is needed to uncover the signalling behind the Golgi checkpoint is the definition of the precise mechanism of action of the proteins involved in Golgi ribbon disassembly during G2. Among the relevant proteins, BARS is probably the only component identified so far with a direct role in this process [27]. BARS is involved in membrane fission at several transport steps, including that from the Golgi complex to the basolateral membrane in epithelial cells, fluid-phase
Significance of the further extensive Golgi disassembly in prophase and metaphase
As mentioned above, at the onset of mitosis, the isolated Golgi stacks resulting from the disassembly of the Golgi complex in G2 are converted into scattered tubulo-reticular elements, and then further fragmented and dispersed throughout the cytoplasm, appearing as the Golgi ‘haze’ (Figure 1) [8, 9, 10]. The fate of these fragments, and the mechanisms by which they are inherited by the two daughter cells, has been explained with two different models.
The first is based on the view that the Golgi
References and recommended reading
Papers of particular interest, published within the annual period of the review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors would like to thank A Luini for insightful discussions, A De Matteis for critical reading of the manuscript, A Persico for providing the confocal image, CP Berrie for editorial assistance, Elena Fontana for preparation of the figures and the Italian Association for Cancer Research (AIRC, Milan, Italy), Telethon (Italy) and the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR, Italy) for financial support.
References (62)
- et al.
Golgins and GTPases, giving identity and structure to the Golgi apparatus
Biochim Biophys Acta
(2005) - et al.
The Golgi apparatus at the cell centre
Curr Opin Cell Biol
(2003) - et al.
COP-coated vesicles are involved in the mitotic fragmentation of Golgi stacks in a cell-free system
J Cell Biol
(1994) - et al.
Signaling via mitogen-activated protein kinase kinase (MEK1) is required for Golgi fragmentation during mitosis
Cell
(1998) - et al.
MEK1-induced Golgi dynamics during cell cycle progression is partly mediated by Polo-like kinase-3
Oncogene
(2004) Golgi reassembly after mitosis: the AAA family meets the ubiquitin family
Biochim Biophys Acta
(2005)- et al.
p37 is a p97 adaptor required for Golgi and ER biogenesis in interphase and at the end of mitosis
Dev Cell
(2006) - et al.
Mitotic Golgi is in a dynamic equilibrium between clustered and free vesicles independent of the ER
Traffic
(2001) - et al.
The Golgi-associated protein GRASP65 regulates spindle dynamics and is essential for cell division
Mol Biol Cell
(2005) - et al.
Functional inactivation of a transcriptional corepressor by a signaling kinase
Nat Struct Biol
(2003)
GRASP65, a protein involved in the stacking of Golgi cisternae
Cell
Mapping the functional domains of the Golgi stacking factor GRASP65
J Biol Chem
YSK1 is activated by the Golgi matrix protein GM130 and plays a role in cell migration through its substrate 14-3-3zeta
J Cell Biol
The physiology of membrane transport and endomembrane-based signalling
EMBO J
RAF1-activated MEK1 is found on the Golgi apparatus in late prophase and is required for Golgi complex fragmentation in mitosis
J Cell Biol
Dispersal of Golgi matrix proteins during mitotic Golgi disassembly
J Cell Sci
The localization and phosphorylation of p47 are important for Golgi disassembly–assembly during the cell cycle
J Cell Biol
A role for the Rab6A′ GTPase in the inactivation of the Mad2-spindle checkpoint
EMBO J
Mitotic phosphorylation of the peripheral Golgi protein Nir2 by Cdk1 provides a docking mechanism for Plk1 and affects cytokinesis completion
Mol Cell
Cytokinesis in plant and animal cells: endosomes ‘shut the door’
Dev Biol
The mammalian Golgi—complex debates
Nat Rev Mol Cell Biol
Tridimensional structure of the Golgi apparatus of nonciliated epithelial cells of the ductuli efferentes in rat: an electron microscope stereoscopic study
Biol Cell
The Golgi mitotic checkpoint is controlled by BARS-dependent fission of the Golgi ribbon into separate stacks in G2
EMBO J
Mitogen-activated protein kinase kinase 1-dependent Golgi unlinking occurs in G2 phase and promotes the G2/M cell cycle transition
Mol Biol Cell
The biogenesis of the Golgi ribbon: the roles of membrane input from the ER and of GM130
Mol Biol Cell
Golgi architecture and inheritance
Annu Rev Cell Dev Biol
Cell-cycle-specific Golgi fragmentation: how and why?
Curr Opin Cell Biol
Molecular basis for Golgi maintenance and biogenesis
Curr Opin Cell Biol
Polo-like kinase is required for the fragmentation of pericentriolar Golgi stacks during mitosis
Proc Natl Acad Sci USA
ERK1c regulates Golgi fragmentation during mitosis
J Cell Biol
Mitotic Golgi partitioning is driven by the membrane-fissioning protein CtBP3/BARS
Science
Cited by (84)
The human VRK1 chromatin kinase in cancer biology
2021, Cancer LettersGolgi ribbon disassembly during mitosis, differentiation and disease progression
2017, Current Opinion in Cell BiologyCitation Excerpt :Furthermore, the disassembly of the ribbon also controls mitotic progression and spindle dynamics [49,50•,51•]. This mutual regulation of Golgi inheritance and cell division ensures the propagation of a functional Golgi ribbon through successive generations [52]. Once committed to mitotic entry, mammalian cells rapidly remodel their cellular structures to prepare for division [53].