Microreviews, Review
The role of transcriptional ‘futile cycles’ in autophagy and microbial pathogenesis
Guowu Hu1, Travis McQuiston1, Amélie Bernard2, Yoon-Dong Park1, Jin Qiu1, Ali Vural3, Nannan Zhang1, Scott R. Waterman1, Nathan H. Blewett4, Timothy G. Myers5, John H. Kehrl3, Gulbu Uzel1, Daniel J. Klionsky2 and Peter R. Williamson1
Eukaryotic cells utilize macroautophagy (hereafter autophagy) to recycle cellular materials during nutrient stress. Target of rapamycin (Tor) is a central regulator of this process, acting by post-translational mechanisms, phosphorylating preformed autophagy-related (Atg) proteins to repress autophagy during log-phase growth. A role for this regulatory process in fungal virulence was further demonstrated by showing that overexpression of the Dcp2-associated mRNA-binding protein Vad1 in the AIDS-associated pathogen Cryptococcus neoformans results in constitutive repression of autophagy even under starvation conditions as well as attenuated virulence in a mouse model. In summary, Tor-dependent post-transcriptional regulation of autophagy plays a key role in the facilitation of microbial pathogenesis.
The many facets of homologous recombination at telomeres
Clémence Claussin and Michael Chang
The ends of linear chromosomes are capped by nucleoprotein structures called telomeres. A dysfunctional telomere may resemble a DNA double-strand break (DSB), which is a severe form of DNA damage. The presence of one DSB is sufficient to drive cell cycle arrest and cell death. Therefore cells have evolved mechanisms to repair DSBs such as homologous recombination (HR). HR-mediated repair of telomeres can lead to genome instability, a hallmark of cancer cells, which is why such repair is normally inhibited. However, some HR-mediated processes are required for proper telomere function. The need for some recombination activities at telomeres but not others necessitates careful and complex regulation, defects in which can lead to catastrophic consequences. Furthermore, some cell types can maintain telomeres via telomerase-independent, recombination-mediated mechanisms. In humans, these mechanisms...
From the baker to the bedside: yeast models of Parkinson’s disease
Regina Menezes1,2, Sandra Tenreiro3,5, Diana Macedo2, Cláudia N. Santos1,2, Tiago Fleming Outeiro4,5,6
The baker’s yeast Saccharomyces cerevisiae has been extensively explored for our understanding of fundamental cell biology processes highly conserved in the eukaryotic kingdom. This review provides a brief historical perspective on the emergence of yeast as an experimental model and on how the field evolved to exploit the potential of the model for tackling the intricacies of various human diseases. In particular, the authors focus on existing yeast models of the molecular underpinnings of Parkinson’s disease (PD), focusing primarily on the central role of protein quality control systems.
Why are essential genes essential? – The essentiality of Saccharomyces genes
Zhaojie Zhang and Qun Ren
Essential genes are defined as required for the survival of an organism or a cell. This article reviews and analyzes the levels of essentiality of the Saccharomyces cerevisiae genes and groups the genes into four categories: (1) Conditional essential: essential only under certain circumstances or growth conditions; (2) Essential: required for survival under optimal growth conditions; (3) Redundant essential: synthetic lethal due to redundant pathways or gene duplication; and (4) Absolute essential: the minimal genes required for maintaining a cellular life under a stress-free environment. The essential and non-essential functions of the essential genes are further analyzed.
Membrane depolarization-triggered responsive diversification leads to antibiotic tolerance
Natalie Verstraeten, Wouter Joris Knapen, Maarten Fauvart, Jan Michiels
In this article, the authors discuss the article "Obg and membrane depolarization are part of a microbial bet-hedging strategy that leads to antibiotic tolerance", Verstraeten et al., Mol. Cell 2015 Jul 2; 59 (1): 9-21.
Evolutionary rewiring of bacterial regulatory networks
Tiffany B. Taylor1,*, Geraldine Mulley1, Liam J. McGuffin1, Louise J. Johnson1, Michael A. Brockhurst2, Tanya Arseneault1,3, Mark W. Silby4 and Robert W. Jackson1,5
Bacteria have evolved complex regulatory networks that enable integration of multiple intracellular and extracellular signals to coordinate responses to environmental changes. However, our knowledge of how regulatory systems function and evolve is still relatively limited. There is often extensive homology between components of different networks, due to past cycles of gene duplication, divergence, and horizontal gene transfer, raising the possibility of cross-talk or redundancy. Consequently, evolutionary resilience is built into gene networks – homology between regulators can potentially allow rapid rescue of lost regulatory function across distant regions of the genome. This article discusses Taylor, et al. Science (2015), 347(6225), reporting mutations that facilitate cross-talk between pathways can contribute to gene network evolution, but which come with severe pleiotropic costs. Arising from this work are a number of questions surrounding how this phenomenon occurs.
Wanted Plasmodium falciparum, dead or alive
Fatimata Sow1, Mary Nyonda1, Anne-Lise Bienvenu1, 2, Stephane Picot1, 2
In this article, mechanisms of cell death in unicellular parasites are discussed, focussing on “programmed cell death” in Plasmodium.
Yeast as a tool to explore cathepsin D function
H. Pereira1, C.S.F. Oliveira1,2, L. Castro1, A. Preto1, S. R. Chaves1,#, M. Côrte-Real1,#
Cathepsin D has garnered increased attention in recent years, mainly since it has been associated with several human pathologies. This review summarizes how cathepsin D can have both anti- and pro-survival functions depending on its proteolytic activity, cellular context and stress stimulus.
Coordinate responses to alkaline pH stress in budding yeast
Albert Serra-Cardona, David Canadell and Joaquín Ariño
This review summarizes the modulation of a substantial number of signaling pathways whose participate in the alkaline response in yeast. These regulatory inputs involve not only the conserved Rim101/PacC pathway, but also the calcium-activated phosphatase calcineurin, the Wsc1-Pkc1-Slt2 MAP kinase, the Snf1 and PKA kinases and oxidative stress-response pathways.
When the pandemic opts for the lockdown: Secretion system evolution in the cholera bacterium
February 18, 2021
This article comments on work published by Santoriello et al. (Nat Comm, 2020), which demonstrates that the T6SS island Auxiliary Cluster 3 (Aux3) is unique to pandemic strains of V. cholerae.
Maintaining phagosome integrity during fungal infection: do or die?
December 3, 2020
This article refers to the paper "Lysosome Fusion Maintains Phagosome Integrity during Fungal Infection" by Westman et al. (Cell Host Microbe, 2020), which shows that macrophages respond to pathogen growth by expanding the phagosome membrane through a calcium-dependent mechanism involving lysosome insertion, maintaining membrane integrity and preventing rupture.
A novel antibacterial strategy: histone and antimicrobial peptide synergy
October 8, 2020
This article refers to the study "Mammalian histones facilitate antimicrobial synergy by disrupting the bacterial proton gradient and chromosome organization" by Doolin et al. (Nat Comm, 2020) that shows that histones enhance the antimicrobial activity of peptides, disrupt bacterial membranes, and inhibit transcription, offering new insights into natural antimicrobial mechanisms.
Erythrocyte phospho-signalling is dynamically altered during infection with Plasmodium falciparum
September 16, 2020
This article refers to the study "Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention" by Adderley et al. (Nat Commun, 2020) that investigates how Plasmodium falciparum malaria parasites influence red blood cells. By tracking hanges in over 800 human proteins at different parasite stages they confirmed activation of the PAK-MEK pathway and discovered significant changes, particularly during the trophozoite stage. This suggests that kinases activated by the infection could be targeted for new antimalarial therapies.
A new role for proteins subunits of RNase P: stabilization of the telomerase holoenzyme
June 17, 2020
This article refers to the study "Stability and Nuclear Localization of Yeast Telomerase Depend on Protein Components of RNase P/MRP", by Garcia et al. (Nat Commun, 2020), showing that 3 essential proteins in Saccharomyces cerevisiae are vital for telomerase assembly and nuclear localization. In their mutants, telomerase is less mature, and telomeres are shorter. TLC1 is properly folded but remains in the cytoplasm, rather than moving to the nucleus, where it maintains telomeres.
Lipid droplet biogenesis from specialized ER subdomains
June 16, 2020
This article refers to the paper "Seipin and Nem1 establish discrete ER subdomains to initiate yeast lipid droplet biogenesis" by Choudhary et al. (J Cell Biol, 2020), which deals with the formation of lipid droplets (LDs) at specific ER sites marked by the proteins Fld1 and Nem1. These proteins recruit enzymes such as Lro1 and Dga1 to initiate fat storage. Together, Fld1 and Nem1 define where LDs form by organising key proteins and lipids needed for their biogenesis.
A broad-spectrum antibiotic adjuvant SLAP-S25: one stone many birds
June 15, 2020
This article refers to the study "A broad-spectrum antibiotic adjuvant reverses multidrug-resistant Gram-negative pathogens" by Song et al. (Nat Microbiol, 2020), which deals with the growing threat of antibiotic resistance, with few new drugs being developed for decades. The study found that the peptide SLAP-S25 enhances the efficacy of several antibiotics against resistant Gram-negative bacteria by disrupting their membranes, thereby increasing drug uptake. This suggests that bacterial membranes are promising targets for new antibiotic adjuvants.
Hiding in plain sight: vesicle-mediated export and transmission of prion-like proteins
June 2, 2020
This article relates to the study "Glucose availability dictates the export of the soluble and prion forms of Sup35p via periplasmic or extracellular vesicles" by Kabani et al. (Mol Microbiol, 2020) that provides compelling evidence that yeast prions, such as Sup35p in its infectious [PSI⁺] state, can be exported via both extracellular vesicles (EVs) and periplasmic vesicles (PVs), with this export being modulated by environmental glucose levels. The discovery that prion particles are released in high amounts through PVs during glucose starvation adds a new dimension to our understanding of prion transmission and opens up fascinating possibilities for exploring vesicle-mediated spread of protein aggregates in neurodegenerative diseases using yeast as a model system.
A novel c-di-GMP signal system regulates biofilm formation in Pseudomonas aeruginosa
April 23, 2020
This article relates to the study "The SiaA/B/C/D signaling network regulates biofilm formation in Pseudomonas aeruginosa" by Chen et al. (EMBO J, 2020) that reveals a novel signaling network encoded by the siaABCD operon in Pseudomonas aeruginosa that regulates biofilm and aggregate formation by controlling the diguanylate cyclase activity of SiaD through phosphorylation-dependent interactions with SiaC, highlighting a potential antimicrobial target.