Selective dephosphorylation by PP2A-B55 directs the meiosis I - meiosis II transition in oocytes
Preprint posted on 21 August 2020 https://www.biorxiv.org/content/10.1101/2020.08.21.260216v1
Article now published in eLife at http://dx.doi.org/10.7554/eLife.70588
Dephosphorylation by PP2A/B55 is important for the meiosis I-meiosis II transitionSelected by Federico Pelisch, Samuel Taylor
Samuel J.P. Taylor & Federico Pelisch
School of Life Sciences – University of Dundee
Oocytes in many organisms, including humans, exist in a prolonged state of arrest during meiotic prophase until stimulated to resume cell division (1). Once stimulated, the oocyte undergoes two successive segregation events to generate haploid gametes. These then fuse with the haploid sperm to begin mitotic divisions consisting of diploid genetic material. The progression from oocyte prophase arrest to embryonic mitotic division must be conducted in an organised and timely manner in order to maintain the integrity of cell division and produce viable gametes. Whilst the importance of phosphorylation and dephosphorylation during cell division has been studied for decades (2), a wider understanding of the global phosphoproteome dynamics throughout the transition from oocyte to embryo remained unclear. In this paper, Swartz et al., investigated the global phosphoproteomic changes that take place during the oocyte to embryo transition. Interestingly, this showed that PP2A:B55 plays a key role in dephosphorylation events required to transition from meiosis I to meiosis II. Furthermore, the preference of PP2A:B55 for phospho-threonines plays an important role in the timely dephosphorylation of substrate proteins during this meiotic transition, as has previously been shown to be important in the regulation of mitotic exit (3-5).
- Protein levels are mostly stable throughout Meiosis: Proteomic analysis showed protein levels changed <2-fold in 98.8% of proteins, with some important exceptions such as cyclin B.
- Phosphorylation levels altered throughout oocyte to embryo transition: Phosphoproteomic analysis showed the changing phosphorylation abundance at different stages of the oocyte to embryo transition, with the lowest point during prophase arrest and peak during meiosis I before falling again for meiosis II (fig. 1). The authors showed that an activating phosphorylation of p42/ERK was not present during prophase arrest but was during meiosis I and II, whilst inhibitory mutations of Cdk1 are high in prophase arrest and low during meiosis. In this manner, phosphorylation regulates the activity of proteins required at different stages within the oocyte to embryo transition.
- Phosphatase activity regulates phosphorylation state throughout the oocyte to embryo transition: Inhibitory phosphorylations of PP1 and PP2A:B55 are low during prophase and high during meiosis I and meiosis II, respectively. Inhibiting phosphatase activity released prophase arrest but did not allow full meiotic progression due to widespread errors in cell division machinery. As such, the regulation of phosphatase activity is important for maintaining the low phosphorylation state during prophase arrest and allowing enhanced phosphorylation during meiosis.
- PP2A:B55 primarily responsible for dephosphorylation events at the meiosis I to meiosis II transition: The authors clustered the phosphoproteomic sites that achieve maximum phosphorylation in meiosis I into sites that are rapidly dephosphorylated by meiosis II, and those that are more slowly dephosphorylated throughout meiosis II and the subsequent stages (fig. 1). Those in the rapidly dephosphorylated cluster were enriched for threonine followed by proline with basic amino acids downstream (TPxK) – a PP2A:B55 consensus sequence (4-6). Disruption of the interaction between substrates and the B55 regulatory subunit resulted in successful meiosis I but disrupted meiosis II, highlighting the importance of PP2A:B55 in meiosis II particularly. This was explored further by substituting T61 of starfish INCENP for a serine residue. Dephosphorylation of T61 is required to translocate INCENP to the central spindle in anaphase, the T61S mutant did not translocate to the central spindle – emphasising the importance of the threonine residue for the timely dephosphorylation by PP2A:B55.
What we liked about the paper
Although many individual examples of the importance of phosphorylation events at different stages of cell division are known, the global overview of how phosphorylation states change throughout the oocyte to embryo transition, as well as the confirmation that overall protein levels remain relatively stable throughout the transition, will be highly useful information. The essential nature of these phosphorylation state changes in maintaining prophase arrest and the fidelity of meiotic progression, as well as the importance of phosphatase activity in regulating these changes, is clearly a fundamentally important balance required throughout the transition from oocyte to embryo. Furthermore, it was particularly interesting how large an effect altering T61 to serine had on INCENP localisation changes in anaphase, highlighting the threonine and serine are not necessarily interchangeable residues despite their similar properties. This builds on previous work indicating phospho-threonines are preferentially dephosphorylated during mitotic exit (3-5).
- Was Securin dynamics measured at all?
- What is the localisation of B55 athroughout these stages?
- Is the enhanced stability of phospho-serines only observed at points where B55 is particularly important or is this a wider characteristic? Could the reason that most sites identified in phosphoproteomic analyses are serine residues (~80%) rather than threonine residues (~20%) reflect phospho-serines being more stable than phospho-threonines in a wider sense?
- Von Stetina, J. R., and Orr-Weaver, T. L. (2011) Developmental control of oocyte maturation and egg activation in metazoan models. Cold Spring Harb. Perspect. Biol. 3, a005553–a005553
- Moura, M., and Conde, C. (2019) Phosphatases in Mitosis: Roles and Regulation. Biomolecules. 9, 55
- Hein, J. B., Hertz, E. P. T., Garvanska, D. H., Kruse, T., and Nilsson, J. (2017) Distinct kinetics of serine and threonine dephosphorylation are essential for mitosis. Nat. Cell Biol. 19, 1433–1440
- Cundell, M. J., Hutter, L. H., Nunes Bastos, R., Poser, E., Holder, J., Mohammed, S., Novak, B., and Barr, F. A. (2016) A PP2A-B55 recognition signal controls substrate dephosphorylation kinetics during mitotic exit. J. Cell Biol. 214, 539–554
- McCloy, R. A., Parker, B. L., Rogers, S., Chaudhuri, R., Gayevskiy, V., Hoffman, N. J., Ali, N., Watkins, D. N., Daly, R. J., James, D. E., Lorca, T., Castro, A., and Burgess, A. (2015) Global Phosphoproteomic Mapping of Early Mitotic Exit in Human Cells Identifies Novel Substrate Dephosphorylation Motifs. Mol. Cell. Proteomics. 14, 2194–2212
Kruse, T., Gnosa, S. P., Nasa, I., Garvanska, D. H., Hein, J. B., Nguyen, H., Samsøe-Petersen, J., Lopez-Mendez, B., Hertz, E. P. T., Schwarz, J., Pena, H. S., Nikodemus, D., Kveiborg, M., Kettenbach, A. N., and Nilsson, J. (2020) Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits. EMBO J. 39, e103695
Posted on: 19 October 2020 , updated on: 20 October 2020
doi: https://doi.org/10.1242/prelights.25250Read preprint
Also in the cell biology category:
BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote replication fork stability and continuous DNA synthesis
Quantification of gallium cryo-FIB milling damage in biological lamella
Coordinated growth of linked epithelia is mediated by the Hippo pathway
preListscell biology category:in the
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
|List by||Sergio Menchero et al.|
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
|List by||Nadja Hümpfer et al.|
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
|List by||Osvaldo Contreras|
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
|List by||Alex Eve|
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
|List by||Ana Dorrego-Rivas|
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
|List by||Ana Dorrego-Rivas|
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
|List by||Dey Lab, Samantha Seah|
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
|List by||Yamini Ravichandran|
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
|List by||Maiko Kitaoka et al.|
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
|List by||Paul Gerald L. Sanchez and Stefano Vianello|
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
|List by||Hiral Shah|
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
|List by||Madhuja Samaddar et al.|
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
|List by||Dey Lab|
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
|List by||Sandra Malmgren Hill|
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
|List by||Rob Hynds|
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
|List by||Pablo Ranea Robles|
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
|List by||Dey Lab|
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
|List by||Sandra Franco Iborra|
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
|List by||Joseph Jose Thottacherry|
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
|List by||Dey Lab, Amanda Haage|