Hsp70 molecular chaperones play a variety of functions in every organism, cell type and organelle, and their activities have been implicated in a number of human pathologies, ranging from cancer to neurodegenerative diseases. The functions, regulations and structure of Hsp70s were intensively studied for about three decades, yet much still remains to be learned about these essential folding enzymes. Genome sequencing efforts revealed that most genomes contain multiple members of the Hsp70 family, some of which co-exist in the same cellular compartment. For example, the human cytosol and nucleus contain six highly homologous Hsp70 proteins while the yeast Saccharomyces cerevisiae contains four canonical Hsp70s and three fungal-specific ribosome-associated and specialized Hsp70s. The reasons and significance of the requirement for multiple Hsp70s is still a subject of debate. It has been postulated for a long time that these Hsp70 isoforms are functionally redundant and differ only by their spatio-temporal expression patterns. However, several studies in yeast and higher eukaryotic organisms challenged this widely accepted idea by demonstrating functional specificity among Hsp70 isoforms. Another element of complexity is brought about by specific cofactors, such as Hsp40s or nucleotide exchange factors that modulate the activity of Hsp70s and their binding to client proteins. Hence, a dynamic network of chaperone/co-chaperone interactions has evolved in each organism to efficiently take advantage of the multiple cellular roles Hsp70s can play. We summarize here our current knowledge of the functions and regulations of these molecular chaperones, and shed light on the known functional specificities among isoforms.

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BackgroundThe cytosol of most eukaryotic cells contains multiple highly conserved Hsp70 orthologs that differ mainly by their spatio-temporal expression patterns. Hsp70s play essential roles in protein folding, transport or degradation, and are major players of cellular quality control processes. However, while several reports suggest that specialized functions of Hsp70 orthologs were selected through evolution, few studies addressed systematically this issue.Methodology/Principal FindingsWe compared the ability of Ssa1p-Ssa4p from Saccharomyces cerevisiae and Ssa5p-Ssa8p from the evolutionary distant yeast Yarrowia lipolytica to perform Hsp70-dependent tasks when expressed as the sole Hsp70 for S. cerevisiae in vivo. We show that Hsp70 isoforms (i) supported yeast viability yet with markedly different growth rates, (ii) influenced the propagation and stability of the [PSI+] and [URE3] prions, but iii) did not significantly affect the proteasomal degradation rate of CFTR. Additionally, we show that individual Hsp70 orthologs did not induce the formation of different prion strains, but rather influenced the aggregation properties of Sup35 in vivo. Finally, we show that [URE3] curing by the overexpression of Ydj1p is Hsp70-isoform dependent.Conclusion/SignificanceDespite very high homology and overlapping functions, the different Hsp70 orthologs have evolved to possess distinct activities that are required to cope with different types of substrates or stress situations. Yeast prions provide a very sensitive model to uncover this functional specialization and to explore the intricate network of chaperone/co-chaperone/substrates interactions.

In its natural habitat, C. elegans encounters a wide variety of microbes, including food, commensals and pathogens. To be able to survive long enough to reproduce, C. elegans has developed a complex array of responses to pathogens. These activities are coordinated on scales that range from individual organelles to the entire organism. Often, the response is triggered within cells, by detection of infection-induced damage, mainly in the intestine or epidermis. C. elegans has, however, a capacity for cell non-autonomous regulation of these responses. This frequently involves the nervous system, integrating pathogen recognition, altering host biology and governing avoidance behaviour. Although there are significant differences with the immune system of mammals, some mechanisms used to limit pathogenesis show remarkable phylogenetic conservation. The past twenty years have witnessed an explosion of host-pathogen interaction studies using C. elegans as a model. This review will discuss the broad themes that have emerged and highlight areas that remain to be fully explored. Natural environment and microbiotaCaenorhabditis elegans is a small free-living nematode found worldwide, predominately in humid, temperate areas where it can feed on the bacteria that proliferate on decaying vegetation (Schulenburg and Félix, 2017). Its natural environment comprises a complex community of microbes, including bacteria, fungi and viruses, including many parasitic species. The effect of environmental microbes on worm fitness can be beneficial, detrimental or mixed (Khan et al., 2018). And as the same microorganism can sometime be either beneficial or detrimental depending on the environmental conditions or the genotype of the host (Gravato-Nobre et al., 2020;Zarate-Potes et al., 2020), we will use the terms of "pathogen" or "commensal" for a given microbe as a simplification.A broad range of microorganisms can infect nematodes in a variety of ways. Different fungi, for example, have independently acquired the capacity to infect worms using diverse strategies (Lebrigand et al., 2016). Some species capture their prey with adhesive structure such as Arthobotrys oligosora or elegant mechanical traps like the constricting rings of al., 2001). Apart from recognition of viral replication products by DRH-1/RIG-1 (Ashe et al., 2013), see below, examples of direct microbial detection that lead to immune pathway activation remain elusive in C. elegans (Kim and Ewbank, 2018).Various molecules from the host, such as the protein HMGB1, formylated peptides, mitochondrial DNA, or uric acid, amongst many others, can also trigger innate immune activity (Tang et al., 2012). Matzinger and colleagues recognized that cells are agnostic with regard to the origin of the damage signals and will respond to them regardless of the preceding event, which led to the 'damage-associated molecular pattern' or DAMP hypothesis (Matzinger, 2002;Seong and Matzinger, 2004). On this basis, the field of innate immunity widened to include recognition of both non-self and se...