Apicomplexan F-actin is required for efficient nuclear entry during host cell invasion
Posted on: 4 June 2019
Preprint posted on 23 May 2019
Article now published in EMBO reports at http://dx.doi.org/10.15252/embr.201948896
How do cells move bulky intracellular organelles through narrow spaces? Parasites might offer some answers to this exciting question.
Selected by Juan QuintanaCategories: cell biology, microbiology
Background & key findings
During the process of cell migration, cells often face mechanical challenges that require an effective strategy to fit in and efficiently pass otherwise bulky intracellular organelles through restricted and narrow spaces (1). The mechanical forces exerted upon the cell (and intracellular organelles) during the process of cell migration might lead to cell and organelle damage, and therefore cells are thought to have evolved sophisticated mechanisms to protect themselves from this mechanical stress (2–4).
One outstanding question in the field is how cells coordinate, move, and protect their nucleus during migration. An interesting model to this intriguing question has recently been proposed in a study led by Mario del Rosario and colleagues in the laboratory of Prof. Markus Meissner using apicomplexan parasites (5). These single-cell organisms, responsible for devastating human diseases such as malaria (Plasmodium spp.) and toxoplasmosis (T. gondii) (6), have evolved sophisticated mechanisms to invade host cells, and require the coordinated action of parasite-specific organelles like the glideosome, secretory organelles such as micronemes and rhoptries, and the parasite cytoskeleton (7). These cellular structures successfully establish a point of contact between the parasite and host cells in a timely and orderly fashion, leading to the formation of a tight junctional (TJ) ring (TJ) between the parasite cell and the host cell (5,7) (Figure 1). Using transgenic parasites expressing protein-tagged actin nanobodies (called “actin chromobodies”), the authors used high-resolution microscopy and real-time imaging to track live parasites during the process of attachment and host cell invasion. The key findings of these studies are summarised in the next section.
Key findings
- Prior invasion of the host cell, F-actin molecules are dynamically transported between the Golgi apparatus and the cell poles in a bidirectional process regulated by Actin Depolymerisation Factor and mediated by calcium-dependent signalling.
- During the process of host cell invasion, F-actin molecules actively polymerise at the posterior pole of the cell as well as in the region adjacent to the TJ. Importantly, the parasite nucleus is surrounded by a continuous meshwork of F-actin that is connected to the posterior pole of the parasite. It is thought that this meshwork confers nuclear protection against mechanical stress.
- The posterior pole of the parasite suffers contraction prior to or during nuclear entry through the TJ, exerting a “pushing” force towards the intracellular space of the host cell.
- Interfering with the machinery associated with F-actin polymerisation, or with other structures such as the actomyosin system, leads to parasites stalling at the host cell surface, drastically impairing host cell invasion.
Why I like this paper and How I believe this moves the field forward?
Firstly, I believe that the authors have approached this challenge using rather fascinating imaging technologies. Similarly, they have provided a much-needed toolkit to understand cytoskeleton dynamics not only in parasites, but that could be directly translated into other model organisms. I personally believe that this article merges novel approaches that are common to basic cell biologists as well as parasitologists, therefore broadening the impact of the study.
Secondly, as the authors stated in the discussion, this article provides, for the first time, compelling evidence to demonstrate the importance of F-actin during host cell invasion, and propose a reconciled model in which this system allows the passage of bulky intracellular organelles through an otherwise rigid and tight junction between the parasite and the host cell. More importantly, the authors also demonstrated that these mechanisms of cell invasion are conserved between two different apicomplexan parasites, thereby suggesting an evolutionary conserved mechanism to deal with physical problems during cell invasion and migration. These observations will change the way in which we explore the initial steps in host cell invasions by intracellular pathogens, and could inform future efforts in developing therapeutic applications aiming at blocking this process.
Open questions to the authors:
How do the different Formins “communicate” during the process of host cell invasion?
Mario del Rosario/Markus Meissner: From the 3 formin proteins currently identified in T. gondii, only Formin-1 has been associated with motility, invasion and egress (Tosetti et al., 2019). We can speculate that nucleated actin in the apical end of the parasite by Formin-1 is transported via myosin H and A (also suggested in Tosetti et al., 2019), translocating as a flow in the periphery and cytosol of the parasite. Once this peripherical flow reaches the basal end of the parasite, a continuum network is formed between cytoplasmic F-actin pools and the peripherical flow as shown in the SR-SIM in this work. Once the cytoplasmatic pools are connected, F-actin association with the nucleus would occur.
Based on our imaging data, we speculate that the activity of the individual Formins is tightly coordinated, by the integration of different signalling cascades. However at this point we can only speculate on this complex regulation and further studies are required to address this important questions.
The process of mechanotransduction regulates many process in the cell, including chromatin conformation and gene expression (1). Do you think that this mechanical stress impacts gene expression? Do you think that the mere process of passing through the TJ might act as a mechanical cue to regulate expression of genes important to adapt to the parasite’s intracellular niche?
Mario del Rosario/Markus Meissner: This is an excellent question we are also excited on exploring as physical deformation of the nucleus has been suggested to alter gene expression in other eukaryotes. So far, in the case of Plasmodium falciparum, perinuclear F-actin has been implicated in antigenic variaton (see Zhang et al., 2011). It will be interesting to study if mechano-transducing cues lead to changes in gene expression, as demonstrated in other eukaryotes. It is possible that nuclear deformation triggers changes in gene expression to adapt from extracellular to intracellular life.
In the model that you proposed, you mentioned that there are some instances where the formation of an F-actin ring is not required for host cell invasion. I was wondering if you have a hypothesis to explain how parasites might sense this “host cell permissiveness”? Do you think the accumulation of the F-actin right at the TJ might be a consequence of a disrupted retrograde transport? Or do you think it is mediated by upstream signalling processes?
Mario del Rosario/Markus Meissner: Our current hypothesis is that the host cell exerts pressure at the TJ resulting in deformation of the parasite, as also suggested by Bichet et al., 2016. It is likely that at this point the parasite is capable to sense deformation/pressure and adjust the accumulation of F-actin in order to provide more force for invasion and stabilise the junction. We do not think it is a disruption of retrograde transport, since accumulation of F-actin at the posterior pole of the parasite (which results from retrograde transport) is always seen, independent of F-actin at the junction.
References
- Maurer M, Lammerding J. The Driving Force: Nuclear Mechanotransduction in Cellular Function, Fate, and Disease. Annu Rev Biomed Eng. 2019;21.
- Martino F, Perestrelo AR, Vinarsky V, Pagliari S, Forte G. Cellular Mechanotransduction: From Tension to Function. Front Physiol. 2018;9.
- Wiche G, Osmanagic-Myers S, Castanon MJ. Networking and anchoring through plectin: a key to IF functionality and mechanotransduction. Curr Opin Cell Biol. 2015;32.
- Toivola DM, Tao G-Z, Habtezion A, Liao J, Omary MB. Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments. Trends Cell Biol. 2005;15.
- Rosario M Del, Periz J, Pavlou G, Lyth O, Latorre-Barragan F, Das S, et al. Apicomplexan F-actin is required for efficient nuclear entry during host cell invasion. bioRxiv. 2019;
- Campo J del, Heger T, Rodríguez-Martínez R, Worden AZ, Richards TA, Massana R, et al. A new framework for the study of apicomplexan diversity across environments. bioRxiv. 2019;
- Besteiro S, Dubremetz J. The moving junction of apicomplexan parasites : a key structure for invasion. Cell Microbiol. 2011;13.
doi: https://doi.org/10.1242/prelights.11053
Read preprintSign up to customise the site to your preferences and to receive alerts
Register hereAlso in the cell biology category:
Germplasm stability in zebrafish requires maternal Tdrd6a and Tdrd6c
Justin Gutkowski
Leukocytes use endothelial membrane tunnels to extravasate the vasculature
Felipe Del Valle Batalla
Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder
Harvey Roweth
Also in the microbiology category:
Green synthesized silver nanoparticles from Moringa: Potential for preventative treatment of SARS-CoV-2 contaminated water
Safieh Shah, Benjamin Dominik Maier
Intracellular diffusion in the cytoplasm increases with cell size in fission yeast
Leeba Ann Chacko, Sameer Thukral
Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA
Leeba Ann Chacko
preListscell biology category:
in theNovember in preprints – the CellBio edition
This is the first community-driven preList! A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. Categories include: 1) cancer cell biology 2) cell cycle and division 3) cell migration and cytoskeleton 4) cell organelles and organisation 5) cell signalling and mechanosensing 6) genetics/gene expression
List by | Felipe Del Valle Batalla et al. |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
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. |
Fibroblasts
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 |
FENS 2020
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 |
1
Cell Polarity
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 |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
List by | Maiko Kitaoka et al. |
3D Gastruloids
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 |
Autophagy
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 |
Cellular metabolism
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 |
MitoList
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 |
Also in the microbiology category:
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 |
1
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
List by | Hiral Shah |
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 |
Antimicrobials: Discovery, clinical use, and development of resistance
Preprints that describe the discovery of new antimicrobials and any improvements made regarding their clinical use. Includes preprints that detail the factors affecting antimicrobial selection and the development of antimicrobial resistance.
List by | Zhang-He Goh |