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Responses to Muscular Exercise, Heat Shock Proteins as Regulators of Inflammation, and Mitochondrial Quality Control
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Alex T. Von Schulze, Paige C. Geiger
HSPs are critical in cell proteostasis through their ability to fold nascent proteins and refold damaged proteins. Importantly, HSP70, HSP40, and HSP90 are all critical in ensuring proteostasis by facilitating proper folding of newly translated proteins exiting ribosomes at the endoplasmic reticulum (ER) (24, 29, 92). Ribosome-associated co-chaperones (MPP1 and HSPA14) transfer nascent proteins to non-ribosomal HSP70 chaperone complexes (HSP70 and HSP40), which facilitate the native folding of proteins requiring a high degree of complex co-translational folding (some subsets may be transferred to HSP90 for further processing via Hsp70-Hsp90 Organizing Protein (HOP)) (88, 92). In addition to the folding of nascent proteins, these HSPs are involved in the refolding of damaged or unfolded proteins. After recognition, recruitment, and transfer of unfolded proteins via co-chaperone HSP40, protein-bound HSP70 undergoes adenosine triphosphate (ATP) cycling via nucleotide exchange factors to cause conformational changes in HSP70—ultimately enabling native folding based on amino acid characteristics (i.e., polarity) (29). If proteins are unable to refold via HSP70, they can be passed along to chaperonins (i.e., HSP60 and HSP10) and/or HSP90 for extended processing. If it is not possible for the protein to fold into its native form via its interactions with these chaperones, it is likely to be tagged for degradation via the ubiquitin–proteasome system (UPS).
The Stress Response and Stress Proteins
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Martin E. Feder, Dawn A. Parsell, Susan L. Lindquist
A key element in this regulatory system is the HSF (heat shock factor) family of transcription factors. In unstressed cells of most eukaryotes, HSF exists as a monomer in the cytoplasm. Upon stress, HSF trimerizes, migrates to the nucleus, and binds to consensus sequences (HSEs, or heat shock elements) in the promoters of the heat-shock genes, thereby relieving the block to transcription. HSEs occur in the promoters of heat-shock genes, including those for hsp70. However, hsp70 is exceptional in that it, either by itself or in combination with other factors, may inhibit HSF-activated transcription in at least two ways: First, it may interact with unbound HSF to inhibit or reverse trimerization. Second, it may interact with HSF trimers bound to HSE, either promoting their dissociation from HSE or otherwise inhibiting their activation of transcription. In any event, hsp70 is a protein that apparently interacts with its own transcription factor to inhibit its own synthesis (and, in so doing, coordinately regulates the expression of other stress proteins). Unfolded proteins apparently compete with HSF monomer for interaction with hsp70. Thus, as unfolded proteins bind hsp70 and thereby derepress HSF activation of transcription, they set the stage for their own rescue or demise. DnaK, the hsp70 homologue of E. coli, plays a similar role in the autoregulation of the stress response in this organism. Several publications provide more detailed entree to this topic.32,33
Roles of Melatonin in Maintaining Mitochondrial Welfare
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Feres José Mocayar Marón, Emiliano Diez, Russel J. Reiter, Walter Manucha
Impaired release and reduced bioavailability of nitric oxide (NO) are associated with inflammatory pathologies. Moreover, a reduced NO release induces Hsp70 with effects against oxidative stress, inflammation, and apoptosis during CVD104. In this context, melatonin improves signal transduction by Akt phosphorylation induction and NO levels in a cardiovascular mice model105. Melatonin increases the heat shock protein response (HSP) as part of its antioxidant protective effects106. Notably, melatonin decreases renal injury by modulation of NO, oxidative markers, and Hsp70 expression107 (Figure 2). Thus, clarifying the signaling pathways and shows the role of Hsp70 is relevant to the application of new treatments. Fujimoto et al. evaluated cytokine production linked to Hsp70 protein levels108. We recently reviewed the opposing actions of extracellular versus intracellular Hsp70 on NF-κB pathway activation109.
Inflammation, oxidative stress and altered heat shock response in type 2 diabetes: the basis for new pharmacological and non-pharmacological interventions
Published in Archives of Physiology and Biochemistry, 2022
Gabriela Elisa Hirsch, Thiago Gomes Heck
Studies also show relationship between heat shock protein (HSP) expression and cellular localisation and DM2 (Sunamoto et al.1998, Xia et al.2008, Abo-Salem et al.2009, Krause et al.2015, Calderwood et al.2016). HSP is a large family of proteins synthesised in response to several physiological stressors (Razzaque and Taguchi 1997, Liu et al.2001, Loeffler and Wolf 2015), including oxidative (Krause 2007) and metabolic stress (Beckmann and Welch 1992). The 72-kDa heat shock protein (HSP70) is the most studied and abundant HSP in mammalian cells, accounting for 1–2% of the cellular protein (Noble et al.2008). HSP70 expression is induced under cellular stress conditions (Ohashi et al.2004, Heck et al.2011), an acting on the maintenance of native protein folding (Mayer and Bukau 2005). In DM2, extracellular HSP70 (a.k.a. eHSP70) levels appear to be elevated due to adiposity and inflammation, whereas intracellular HSP70 (a.k.a. iHSP70) levels appear to be decreased (Sunamoto et al.1998, Xia et al.2008, Abo-Salem et al.2009, Calderwood et al.2016). The eHSP70 and iHSP70 alterations are associated with chronic inflammation, reduction of insulin signalling (Xiao et al.2012, Zhu et al.2016) and the insulin resistance development (Razzaque and Taguchi 1997, Bellaye et al.2014).
Acute exposure of glyphosate-based herbicide induced damages on common carp organs via heat shock proteins-related immune response and oxidative stress
Published in Toxin Reviews, 2021
Yuanyuan Li, Weikai Ding, Xiaoyu Li
Heat shock proteins (HSPs) are a family of highly conserved proteins including the small HSPs (sHSPs), the HSP70 superfamily, and HSP90 (Heikkila 2010). The HSP70 family is the most frequently studied HSPs, which are mainly encoded by two genes, a constitutive (HSC70) and stress-inducible (HSP70) genes (Xing et al.2013). These two HSP70s play crucial roles in synergetic immunity, antioxidant, molecular chaperone, and other biological functions (Basu 2002), and HSP90 also has many biological functions, such as protein folding, unfolding, degradation, aggregation, and remodeling of protein complexes, and cells defending against exogenous stresses (Sørensen et al.2003). Therefore, they are commonly used by environmental toxicologists as indicators or biomarkers for early warning of stress condition of exposure to various physical, chemical, and biological stressors, such as metals, pesticides, and pathogen infection (Lindquist and Craig 1988, Bhargav et al.2008, Jing et al.2013, Mrdaković et al.2016, Ma et al.2018a).
Hsp70 modulates immune response in pancreatic cancer through dendritic cells
Published in OncoImmunology, 2021
Bhuwan Giri, Prateek Sharma, Tejeshwar Jain, Anthony Ferrantella, Utpreksha Vaish, Siddharth Mehra, Bharti Garg, Srikanth Iyer, Vrishketan Sethi, Zoe Malchiodi, Rossana Signorelli, Harrys K.C Jacob, John George, Preeti Sahay, Ejas P. Bava, Rajinder Dawra, Sundaram Ramakrishnan, Ashok Saluja, Vikas Dudeja
Heat shock proteins are part of an evolutionarily conserved cellular machinery, which are geared toward protecting cells and tissues from various stresses, including thermal distress.11 Heat Shock Protein 70, or Hsp70, is a member of heat shock protein family, which is ubiquitously expressed in a variety of cell types.12 We have previously demonstrated that Hsp70 is overexpressed in pancreatic cancer cells and that it plays a prosurvival and antiapoptotic role in pancreatic cancer epithelial cells. However, the role of Hsp70 in the TME is unknown.13 In the current study, we have investigated the role of Hsp70 in TME in the progression of cancer. Our results suggest that selective genetic deletion of Hsp70 in the TME significantly attenuates tumor growth. Our results also suggest that this effect is due to the deletion of Hsp70 in immune cellsand not due to depletion of Hsp70 in CAFs. Using a combination of in vitro and in vivo approaches, we demonstrate that lack of Hsp70 in dendritic cells energizes the antigen presentation machinery, which, in turn, leads to the development of a robust anticancer immune response. These findings pave the way for a more complete understanding in modulating and designing effective therapeutic approaches that can complement immunotherapy and dendritic cell vaccination against pancreatic cancer.