Biology of the Cell最新文献

Much attention has been dedicated to understanding how cells sense and respond to mechanical forces. The types of forces cells experience as well as the repertoire of cell surface receptors that sense these forces have been identified. Key mechanisms for transmitting that force to the cell interior have also emerged. Yet, how cells process mechanical information and integrate it with other cellular events remains largely unexplored. Here we review the mechanisms underlying mechanotransduction at cell-cell and cell-matrix adhesions, and we summarize the current understanding of how cells integrate information from the distinct adhesion complexes with cell metabolism.

At first glance, the structure of a microtubule is simple. Globular α- and β-tubulin subunits form constitutive heterodimers that align head-to-tail in protofilaments. In the most common configuration, 13 protofilaments associate laterally with a slight longitudinal stagger that results in a left-handed 3-start helix featuring lateral associations between tubulin subunits. This seemingly straightforward description is actually based on almost half a century of research aimed at understanding how tubulin dimers interact within the microtubule lattice. But while we start to have a good overview of their architecture in vitro, our knowledge of microtubule-lattice organization in vivo is nowhere near to being complete.

Protein folding and protein maturation largely occur in the controlled environment of the Endoplasmic Reticulum (ER). Perturbation to the correct functioning of this organelle leads to altered proteostasis and accumulation of misfolded proteins in the ER lumen. This condition is commonly known as ER stress and is appearing as an important contributor in the pathogenesis of several human diseases. Monitoring of the quality control processes is mediated by the Unfolded Protein Response (UPR). This response consists in a complex network of signalling pathways that aim to restore protein folding and ER homeostasis. Conditions in which UPR is not able to overcome ER stress lead to a switch of the UPR signalling program from an adaptive to a pro-apoptotic one, revealing a key role of UPR in modulating cell fate decisions. Because of its high complexity and its involvement in the regulation of different cellular outcomes, UPR has been the centre of the development of computational models, which tried to better dissect the role of UPR or of its specific components in several contexts. In this review, we go through the existing mathematical models of UPR. We emphasize how their study contributed to an improved characterization of the role of this intricate response in the modulation of cellular functions.

The human immunodeficiency virus type 1 (HIV-1) is an intracellular pathogen whose replication cycle strictly depends on the host cell molecular machinery. HIV-1 crosses twice the plasma membrane, to get in and to get out of the cell. Therefore, the first and the last line of intracellular component encountered by the virus is the cortical actin network. Here, we review the role of actin and actin-related proteins in HIV-1 entry, assembly, budding, and release. We first highlight the mechanisms controlling actin polymerization at the entry site that promote the clustering of HIV-1 receptors, a crucial step for the virus to fuse with the plasma membrane. Then, we describe how actin is transiently depolymerized locally to allow the capsid to cross the actin cortex, before migrating towards the nucleus. Finally, we review the role of several actin-binding proteins in actin remodeling events required for membrane deformation and curvature at the viral assembly site as well as for virus release. Strikingly, it appears that common actin-regulating pathways are involved in viral entry and exit. However, while the role of actin remodeling during entry is well understood, this is not the case during exit. We discuss remaining challenges regarding the actin-dependent mechanisms involved in HIV-1 entry and exit, and how they could be overcome.

Single Virus Tracking (SVT) is a key technique to understand how individual viral particles evolve during the infection cycle. In the case of the human immunodeficiency virus (HIV-1), this technology, which can be employed using a simple and affordable wide-field microscope, has proven to be very useful in the first steps of infection, such as the kinetics of the fusion reaction or the point of fusion within live cells. Here, we describe how SVT in combination with other spectral imaging approaches is a powerful technique to illuminate crucial mechanistic aspects of the HIV-1 fusion reaction. We also stress the role of our laboratory in elucidating a few mechanistic aspects of retroviral fusion employing SVT such as: (i) the role of dynamin, (ii) how metabolism modulates membrane composition and cholesterol and its impact in fusion, (iii) the importance of envelope glycoprotein (Env) intra- and inter-molecular dynamics for neutralization, or (iv) the time-resolved fusion stoichiometry in three characteristic steps for the HIV-1 prefusion step. These observations constitute a good testimony of the complexity of retroviral fusion and show the strength of SVT when applied to live cells and combined with quantitative spectral approaches. Finally, we propose several crucial remaining questions around HIV-1 fusion and how the combined use of these technologies, always in live cells, will be able to shed light into the intricacies of arguably the most important step of the HIV-1 infection cycle.

SARS-CoV-2 is a human pathogenic virus responsible for the COVID-19 (coronavirus disease 2019) pandemic. The infection cycle of SARS-CoV-2 involves several related steps, including virus entry, gene expression, RNA replication, assembly of infectious virions and their egress. For all of these steps, the virus relies on and exploits host cell factors, cellular organelles, and processes such as endocytosis, nuclear transport, protein secretion, metabolite transport at membrane contact sites (MSC) and exocytotic pathways. To do this, SARS-CoV-2 has evolved multifunctional viral proteins that hijack cellular factors and modulate their function by unique strategies. In this Review, we highlight cellular trafficking factors, processes, and organelles of relevance to the SARS-CoV-2 infection cycle and how viral proteins make use of and perturb cellular transport during the viral infection cycle.