The HOG pathway and the regulation of osmoadaptive responses in yeast

Cells coordinate intracellular activities in response to changes in the extracellular environment to maximize their probability of survival and proliferation. Eukaryotic cells need to adapt to constant changes in the osmolarity of their environment. In yeast, the high-osmolarity glycerol (HOG) pathway is responsible for the response to high osmolarity. Activation of the Hog1 stress-activated protein kinase (SAPK) induces a complex program required for cellular adaptation that includes temporary arrest of cell cycle progression, adjustment of transcription and translation patterns, and the regulation of metabolism, including the synthesis and retention of the compatible osmolyte glycerol. Hog1 is a member of the family of p38 SAPKs, which are present across eukaryotes. Many of the properties of the HOG pathway and downstream-regulated proteins are conserved from yeast to mammals. This review addresses the global view of this signaling pathway in yeast, as well as the contribution of Dr Hohmann's group to its understanding.The laboratories of FP and EdN are supported by grants from the Ministry of Science, Innovation and Universities (PGC2018-094136-B-I00 to FP; BFU2017-85152-P and FEDER to EdN) and the Government of Catalonia (2017 SGR 799). We gratefully acknowledge institutional funding from the Ministry of Science, Innovation and Universities through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Government of Catalonia and the Unidad de Excelencia María de Maeztu, funded by the AEI (CEX2018-000792-M). FP and EdN are recipients of ICREA Acadèmia awards (Government of Catalonia)

Osmostress-induced gene expression--a model to understand how stress-activated protein kinases (SAPKs) regulate transcription

Adaptation is essential for maximizing cell survival and for cell fitness in response to sudden changes in the environment. Several aspects of cell physiology change during adaptation. Major changes in gene expression are associated with cell exposure to environmental changes, and several aspects of mRNA biogenesis appear to be targeted by signaling pathways upon stress. Exhaustive reviews have been written regarding adaptation to stress and regulation of gene expression. In this review, using osmostress in yeast as a prototypical case study, we highlight those aspects of regulation of gene induction that are general to various environmental stresses as well as mechanistic aspects that are potentially conserved from yeast to mammals.The laboratory of F.P. and E.N. is supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2012-33503 and FEDER, BFU2014-52125-REDT and BFU2014-51672-REDC to F.P. and BFU2014-52333-P to E.N.), the Catalan Government (2014 SGR 599) and an ERC Advanced Grant (number 294294) from the EU seventh framework program (SYNCOM) to F.P. This project is supported by the Fundación Botín and by Banco Santander through its Santander Universities Global Division to F.P. F.P. and E.N. are recipients of an ICREA Acadèmia (Generalitat de Catalunya)

Osmostress-induced gene expression--a model to understand how stress-activated protein kinases (SAPKs) regulate transcription

Adaptation is essential for maximizing cell survival and for cell fitness in response to sudden changes in the environment. Several aspects of cell physiology change during adaptation. Major changes in gene expression are associated with cell exposure to environmental changes, and several aspects of mRNA biogenesis appear to be targeted by signaling pathways upon stress. Exhaustive reviews have been written regarding adaptation to stress and regulation of gene expression. In this review, using osmostress in yeast as a prototypical case study, we highlight those aspects of regulation of gene induction that are general to various environmental stresses as well as mechanistic aspects that are potentially conserved from yeast to mammals.The laboratory of F.P. and E.N. is supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2012-33503 and FEDER, BFU2014-52125-REDT and BFU2014-51672-REDC to F.P. and BFU2014-52333-P to E.N.), the Catalan Government (2014 SGR 599) and an ERC Advanced Grant (number 294294) from the EU seventh framework program (SYNCOM) to F.P. This project is supported by the Fundación Botín and by Banco Santander through its Santander Universities Global Division to F.P. F.P. and E.N. are recipients of an ICREA Acadèmia (Generalitat de Catalunya)

The rise of single-cell transcriptomics in yeast

The field of single-cell omics has transformed our understanding of biological processes and is constantly advancing both experimentally and computationally. One of the most significant developments is the ability to measure the transcriptome of individual cells by single-cell RNA-seq (scRNA-seq), which was pioneered in higher eukaryotes. While yeast has served as a powerful model organism in which to test and develop transcriptomic technologies, the implementation of scRNA-seq has been significantly delayed in this organism, mainly because of technical constraints associated with its intrinsic characteristics, namely the presence of a cell wall, a small cell size and little amounts of RNA. In this review, we examine the current technologies for scRNA-seq in yeast and highlight their strengths and weaknesses. Additionally, we explore opportunities for developing novel technologies and the potential outcomes of implementing single-cell transcriptomics and extension to other modalities. Undoubtedly, scRNA-seq will be invaluable for both basic and applied yeast research, providing unique insights into fundamental biological processes.The laboratories of FP and EdeN are supported by a coordinated grant from the Ministry of Science, Innovation, and Universities (PID2021-124723NB-C21/C22 and FEDER). We also gratefully acknowledge institutional funding from the Ministry of Science, Innovation and Universities through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Government of Catalonia and the Unidad de Excelencia María de Maeztu, funded by the AEI (CEX2018-000792-M)

Dealing with transcriptional outbursts during S phase to protect genomic integrity

Transcription during S phase needs to be spatially and temporally regulated to prevent collisions between the transcription and replication machineries. Cells have evolved a number of mechanisms to make both processes compatible under normal growth conditions. When conflict management fails, the head-on encounter between RNA and DNA polymerases results in genomic instability unless conflict resolution mechanisms are activated. Nevertheless, there are specific situations in which cells need to dramatically change their transcriptional landscape to adapt to environmental challenges. Signal transduction pathways, such as stress-activated protein kinases (SAPKs), serve to regulate gene expression in response to environmental insults. Prototypical members of SAPKs are the yeast Hog1 and mammalian p38. In response to stress, p38/Hog1 SAPKs control transcription and also regulate cell cycle progression. When yeast cells are stressed during S phase, Hog1 promotes gene induction and, remarkably, also delays replication by directly affecting early origin firing and fork progression. Therefore, by delaying replication, Hog1 plays a key role in preventing conflicts between RNA and DNA polymerases. In this review, we focus on the genomic determinants and mechanisms that make compatible transcription with replication during S phase to prevent genomic instability, especially in response to environmental changes.The laboratory of F.P. and E.N. is supported by grants from the Spanish Government (BFU2012-33503 and FEDER to F.P.; BFU2011-26722 to E.N.), the Consolider Ingenio 2010 program CSD2007-0015 and the Fundación Marcelino Botín to F.P. F.P. and E.N. are recipients of an Institució Catalana de Recerca i Estudis Avançats Acadèmia (Generalitat de Catalunya)

A novel role for lncRNAs in cell cycle control during stress adaptation

Eukaryotic cells have developed sophisticated systems to constantly monitor changes in the extracellular environment and to orchestrate a proper cellular response. To maximize survival, cells delay cell-cycle progression in response to environmental changes. In response to extracellular insults, stress-activated protein kinases (SAPKs) modulate cell-cycle progression and gene expression. In yeast, osmostress induces activation of the p38-related SAPK Hog1, which plays a key role in reprogramming gene expression upon osmostress. Genomic analysis has revealed the existence of a large number of long non-coding RNAs (lncRNAs) with different functions in a variety of organisms, including yeast. Upon osmostress, hundreds of lncRNAs are induced by the SAPK p38/Hog1. One gene that expresses Hog1-dependent lncRNA in an antisense orientation is the CDC28 gene, which encodes CDK1 kinase that controls the cell cycle in yeast. Cdc28 lncRNA mediates the induction of CDC28 expression and this increase in the level of Cdc28 results in more efficient re-entry of the cells into the cell cycle after stress. Thus, the control of lncRNA expression as a new mechanism for the regulation of cell-cycle progression opens new avenues to understand how stress adaptation can be accomplished in response to changing environments.The laboratory of FP and EN is supported by grants from the Spanish Government (BFU2012-33503 and FEDER to FP, BFU2011-26722 to EN), an ERC Advanced Grant Number 294294 from the EU seventh framework program (SYNCOM) and the Fundación Marcelino Botín (FMB) to FP. FP and EN are recipients of an ICREA Acadèmia (Generalitat de Catalunya). The authors declare no competing financial interes

Understanding retinoblastoma post-translational regulation for the design of targeted cancer therapies

The retinoblastoma protein (Rb1) is a prototypical tumor suppressor protein whose role was described more than 40 years ago. Together with p107 (also known as RBL1) and p130 (also known as RBL2), the Rb1 belongs to a family of structurally and functionally similar proteins that inhibits cell cycle progression. Given the central role of Rb1 in regulating proliferation, its expression or function is altered in most types of cancer. One of the mechanisms underlying Rb-mediated cell cycle inhibition is the binding and repression of E2F transcription factors, and these processes are dependent on Rb1 phosphorylation status. However, recent work shows that Rb1 is a convergent point of many pathways and thus the regulation of its function through post-translational modifications is more complex than initially expected. Moreover, depending on the context, downstream signaling can be both E2F-dependent and -independent. This review seeks to summarize the most recent research on Rb1 function and regulation and discuss potential avenues for the design of novel cancer therapies.This project received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie PROBIST grant agreement No. 754510 (postdoctoral fellowship to R.J.) and from BIST Living Allowance Fellowship to A.T.-S. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness [BFU2017-85152-P and FEDER to E.d.N. and PGC2018-094136-B-I00 and FEDER to F.P.], the AECC Foundation [PROYE18010POSA to F.P.] and the Government of Catalonia [2017 SGR 799 to E.d.N. and F.P.]. E.d.N. and F.P. are recipients of ICREA Acadèmia awards (Government of Catalonia). We gratefully acknowledge institutional funding from the Ministry of Science, Innovation and Universities through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Government of Catalonia and the Unidad de Excelencia María de Maeztu, funded by the AEI (CEX2018-000792-M)

The regulation of Net1/Cdc14 by the Hog1 MAPK upon osmostress unravels a new mechanism regulating mitosis

During evolution, cells have developed a plethora of mechanisms to optimize survival in a changing and unpredictable environment. In this regard, they have evolved networks that include environmental sensors, signaling transduction molecules and response mechanisms. Hog1 (yeast) and p38 (mammals) stress-activated protein kinases (SAPKs) are activated upon stress and they drive a full collection of cell adaptive responses aimed to maximize survival. SAPKs are extensively used to learn about the mechanisms through which cells adapt to changing environments. In addition to regulating gene expression and metabolism, SAPKs control cell cycle progression. In this review, we will discuss the latest findings related to the SAPK-driven regulation of mitosis upon osmostress in yeast