Abstract:The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. Natural Hsp104 variants might exist with enhanced, selective activity against neurodegenerative disease substrates. However, natural Hsp104 variation remains largely unexplored. Here, we screened a cross-kingdom collection of Hsp104 homologs in yeast proteotoxicity models. Prokaryotic ClpG reduced TDP-43, FUS, and α-synuclein toxicity, whereas prokaryotic ClpB and hyperactive variants were ine… Show more
“…Conversely, the demonstrated ability of tLST-encoded proteins to prevent protein aggregation, or to restore aggregated proteins to their native state may be an asset in biotechnological applications that aim to achieve high-yield production of heterologously expressed proteins ( Guzzo, 2012 ). Those characteristics might be extended to clinical applications as ClpG also prevents toxicity of protein substrates involved in neurogenerative diseases ( March et al, 2020 ). Moreover, while core genome heat shock proteins are often essential genes, tLST encoded heat shock proteins are accessory genes and thus provide an excellent tool to study the role of protein homeostasis in bacterial stress resistance and ecology.…”
The transmissible locus of stress tolerance (tLST) is found mainly in beta- and gamma-Proteobacteria and confers tolerance to elevated temperature, pressure, and chlorine. This genomic island, previously referred to as transmissible locus of protein quality control or locus of heat resistance likely originates from an environmental bacterium thriving in extreme habitats, but has been widely transmitted by lateral gene transfer. Although highly conserved, the gene content on the island is subject to evolution and gene products such as small heat shock proteins are present in several functionally distinct sequence variants. A number of these genes are xenologs of core genome genes with the gene products to widen the substrate spectrum and to be highly (complementary) expressed thus their functionality to become dominant over core genome genes. In this review, we will present current knowledge of the function of core tLST genes and discuss current knowledge on selection and counter-selection processes that favor maintenance of the tLST island, with frequent acquisition of gene products involved in cyclic di-GMP signaling, in different habitats from the environment to animals and plants, processed animal and plant products, man-made environments, and subsequently humans.
“…Conversely, the demonstrated ability of tLST-encoded proteins to prevent protein aggregation, or to restore aggregated proteins to their native state may be an asset in biotechnological applications that aim to achieve high-yield production of heterologously expressed proteins ( Guzzo, 2012 ). Those characteristics might be extended to clinical applications as ClpG also prevents toxicity of protein substrates involved in neurogenerative diseases ( March et al, 2020 ). Moreover, while core genome heat shock proteins are often essential genes, tLST encoded heat shock proteins are accessory genes and thus provide an excellent tool to study the role of protein homeostasis in bacterial stress resistance and ecology.…”
The transmissible locus of stress tolerance (tLST) is found mainly in beta- and gamma-Proteobacteria and confers tolerance to elevated temperature, pressure, and chlorine. This genomic island, previously referred to as transmissible locus of protein quality control or locus of heat resistance likely originates from an environmental bacterium thriving in extreme habitats, but has been widely transmitted by lateral gene transfer. Although highly conserved, the gene content on the island is subject to evolution and gene products such as small heat shock proteins are present in several functionally distinct sequence variants. A number of these genes are xenologs of core genome genes with the gene products to widen the substrate spectrum and to be highly (complementary) expressed thus their functionality to become dominant over core genome genes. In this review, we will present current knowledge of the function of core tLST genes and discuss current knowledge on selection and counter-selection processes that favor maintenance of the tLST island, with frequent acquisition of gene products involved in cyclic di-GMP signaling, in different habitats from the environment to animals and plants, processed animal and plant products, man-made environments, and subsequently humans.
“…Thus, potentiated Hsp104 variants have been generated by engineering an autoregulatory domain ( Jackrel and Shorter, 2015 ). These enhanced Hsp104 variants can rescue toxicity caused by α-synuclein, FUS and TDP-43 in yeast, Caenorhabditis elegans and mammalian cell model systems ( Jackrel et al, 2014 ; Mack et al, 2020 preprint; March et al, 2020 ; Yasuda et al, 2017 ). Fig.…”
Section: Hsp104mentioning
confidence: 99%
“…Our group has also recently described natural Hsp104 variants that rescue the toxicity of α-synuclein and TDP-43 in an ATPase-independent manner ( March et al, 2020 ). In this study, March et al surveyed the natural sequence space of homologous Hsp104 proteins and found that Hsp104 proteins from diverse species can selectively chaperone α-synuclein in yeast and C. elegans , or TDP-43 in yeast and human cells, without off-target toxicity ( March et al, 2020 ). These naturally enhanced variants did not display enhanced disaggregase activity in vitro , nor did they stringently require ATP binding and hydrolysis to rescue proteotoxicity in yeast.…”
Section: Hsp104mentioning
confidence: 99%
“…These naturally enhanced variants did not display enhanced disaggregase activity in vitro , nor did they stringently require ATP binding and hydrolysis to rescue proteotoxicity in yeast. Rather, they passively inhibited the aggregation of specific substrates ( March et al, 2020 ). Hsp104 variants that do not require excessive ATPase activity for potentiated disaggregase activity are an exciting prospect, as they would be less energetically taxing on degenerating neurons that may already be afflicted by ATP depletion.…”
Neurodegenerative diseases and other protein-misfolding disorders represent a longstanding biomedical challenge, and effective therapies remain largely elusive. This failure is due, in part, to the recalcitrant and diverse nature of misfolded protein conformers. Recent work has uncovered that many aggregation-prone proteins can also undergo liquid–liquid phase separation, a process by which macromolecules self-associate to form dense condensates with liquid properties that are compositionally distinct from the bulk cellular milieu. Efforts to combat diseases caused by toxic protein states focus on exploiting or enhancing the proteostasis machinery to prevent and reverse pathological protein conformations. Here, we discuss recent advances in elucidating and engineering therapeutic agents to combat the diverse aberrant protein states that underlie protein-misfolding disorders.
“…Although metazoans lack an Hsp104 homolog, it was hypothesized that Hsp104 might be active against proteins that aggregate in human disease due to the conserved fold of amyloid and prion-like proteins. While activity of Hsp104 against many human disease-associated proteins is weak, potentiated variants of Hsp104 have been engineered that can prevent and reverse the misfolding of diverse proteins including TDP-43, FUS, and α-Syn [198][199][200][201][202][203][204][205][206][207][208][209][210][211]. Potentiated Hsp104 variants also displayed therapeutic activity in worm and mammalian cell models of neurodegenerative disease [198,212,213].…”
Section: Protein Chaperones To Counter Aberrant Phase Transitionsmentioning
Aberrant protein folding underpins many neurodegenerative diseases as well as certain myopathies and cancers. Protein misfolding can be driven by the presence of distinctive prion and prion-like regions within certain proteins. These prion and prion-like regions have also been found to drive liquid-liquid phase separation. Liquid-liquid phase separation is thought to be an important physiological process, but one that is prone to malfunction. Thus, aberrant liquid-to-solid phase transitions may drive protein aggregation and fibrillization, which could give rise to pathological inclusions. Here, we review prions and prion-like proteins, their roles in phase separation and disease, as well as potential therapeutic approaches to counter aberrant phase transitions.
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