Mitosis controls the Golgi and the Golgi controls mitosis

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In mammals, the Golgi complex is structured in the form of a continuous membranous system composed of up to 100 stacks connected by tubular bridges, the ‘Golgi ribbon’. During mitosis, the Golgi undergoes extensive fragmentation through a multistage process that allows its correct partitioning and inheritance by daughter cells. Strikingly, this Golgi fragmentation is required not only for inheritance but also for mitotic entrance itself, since its block results in the arrest of the cell cycle in G2. This is called the ‘Golgi mitotic checkpoint’. Recent studies have identified the severing of the ribbon into its constituent stacks during early G2 as the precise stage of Golgi fragmentation that controls mitotic entry. This opens new ways to elucidate the mechanism of the Golgi checkpoint.

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.

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