Apicomplexan F-actin is required for efficient nuclear entry during host cell invasion
Preprint posted on May 23, 2019 https://www.biorxiv.org/content/10.1101/646463v1
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.
- 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.
- 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.
Posted on: 4th June 2019Read preprint
Also in the cell biology category:
Cyp26b1 is required for proper airway epithelial differentiation during lung development
|Selected by||Julio Sainz de Aja|
Modulation of β-catenin levels is critical for cranial neural crest patterning and dispersal into first pharyngeal arch
|Selected by||Sruthi Balakrishnan|
Arl13b regulates Sonic Hedgehog signaling from outside primary cilia
|Selected by||Alex Eve|
Also in the microbiology category:
A modification to the life cycle of the parasite Trypanosoma brucei
|Selected by||Mariana De Niz|
Octopi: Open configurable high-throughput imaging platform for infectious disease diagnosis in the field
|Selected by||Mariana De Niz|
Maternal effects and environmental filtering shape seed fungal communities in oak trees
|Selected by||Kiran Gurung|
preListscell biology category:in the
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||Gautam Dey|
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||Gautam Dey, Amanda Haage|
Also in the microbiology category:
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|