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      The heat shock protein family gene Hspa1l in male mice is dispensable for fertility

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          Abstract

          Background

          Heat shock protein family A member 1 like ( Hspa1l) is a member of the 70kD heat shock protein ( Hsp70) family. HSPA1L is an ancient, evolutionarily conserved gene with a highly conserved domain structure. The gene is highly abundant and constitutively expressed in the mice testes. However, the role of Hspa1l in the testes has still not been elucidated.

          Methods

          Hspa1l-mutant mice were generated using the CRISPR/Cas9 system. Histological and immunofluorescence staining were used to analyze the phenotypes of testis and epididymis. Apoptotic cells were detected through TUNEL assays. Fertility and sperm motilities were also tested. Quantitative RT-PCR was used for analyzing of candidate genes expression. Heat treatment was used to induce heat stress of the testis.

          Results

          We successfully generated Hspa1l knockout mice. Hspa1l -/- mice exhibited normal development and fertility. Further, Hspa1l -/- mice shown no significant difference in spermatogenesis, the number of apoptotic cells in testes epididymal histology, sperm count and sperm motility from Hspa1l +/+ mice. Moreover, heat stress does not exacerbate the cell apoptosis in Hspa1l -/- testes. These results revealed that HSPA1L is not essential for physiological spermatogenesis, nor is it involved in heat-induced stress responses, which provides a basis for further studies.

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          Hsp70 chaperones: Cellular functions and molecular mechanism

          M P Mayer, B. Bukau (2005)
          Abstract. Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.
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            The human HSP70 family of chaperones: where do we stand?

            Jürgen Radons (2016)
            The 70-kDa heat shock protein (HSP70) family of molecular chaperones represents one of the most ubiquitous classes of chaperones and is highly conserved in all organisms. Members of the HSP70 family control all aspects of cellular proteostasis such as nascent protein chain folding, protein import into organelles, recovering of proteins from aggregation, and assembly of multi-protein complexes. These chaperones augment organismal survival and longevity in the face of proteotoxic stress by enhancing cell viability and facilitating protein damage repair. Extracellular HSP70s have a number of cytoprotective and immunomodulatory functions, the latter either in the context of facilitating the cross-presentation of immunogenic peptides via major histocompatibility complex (MHC) antigens or in the context of acting as "chaperokines" or stimulators of innate immune responses. Studies have linked the expression of HSP70s to several types of carcinoma, with Hsp70 expression being associated with therapeutic resistance, metastasis, and poor clinical outcome. In malignantly transformed cells, HSP70s protect cells from the proteotoxic stress associated with abnormally rapid proliferation, suppress cellular senescence, and confer resistance to stress-induced apoptosis including protection against cytostatic drugs and radiation therapy. All of the cellular activities of HSP70s depend on their adenosine-5'-triphosphate (ATP)-regulated ability to interact with exposed hydrophobic surfaces of proteins. ATP hydrolysis and adenosine diphosphate (ADP)/ATP exchange are key events for substrate binding and Hsp70 release during folding of nascent polypeptides. Several proteins that bind to distinct subdomains of Hsp70 and consequently modulate the activity of the chaperone have been identified as HSP70 co-chaperones. This review focuses on the regulation, function, and relevance of the molecular Hsp70 chaperone machinery to disease and its potential as a therapeutic target.
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              The HSP70 family and cancer.

              Maureen E Murphy (2013)
              The HSP70 family of heat shock proteins consists of molecular chaperones of approximately 70kDa in size that serve critical roles in protein homeostasis. These adenosine triphosphatases unfold misfolded or denatured proteins and can keep these proteins in an unfolded, folding-competent state. They also protect nascently translating proteins, promote the cellular or organellar transport of proteins, reduce proteotoxic protein aggregates and serve general housekeeping roles in maintaining protein homeostasis. The HSP70 family is the most conserved in evolution, and all eukaryotes contain multiple members. Some members of this family serve specific organellar- or tissue-specific functions; however, in many cases, these members can function redundantly. Overall, the HSP70 family of proteins can be thought of as a potent buffering system for cellular stress, either from extrinsic (physiological, viral and environmental) or intrinsic (replicative or oncogenic) stimuli. As such, this family serves a critical survival function in the cell. Not surprisingly, cancer cells rely heavily on this buffering system for survival. The overwhelming majority of human tumors overexpress HSP70 family members, and expression of these proteins is typically a marker for poor prognosis. With the proof of principle that inhibitors of the HSP90 chaperone have emerged as important anticancer agents, intense focus has now been placed on the potential for HSP70 inhibitors to assume a role as a significant chemotherapeutic avenue. In this review, the history, regulation, mechanism of action and role in cancer of the HSP70 family are reviewed. Additionally, the promise of pharmacologically targeting this protein for cancer therapy is addressed.
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                Author and article information

                Contributors
                Zuomin Zhou
                Mingxi Liu
                Journal
                Journal ID (nlm-ta): PeerJ
                Journal ID (iso-abbrev): PeerJ
                Journal ID (publisher-id): peerj
                Journal ID (pmc): peerj
                Title: PeerJ
                Publisher: PeerJ Inc. (San Diego, USA )
                ISSN (Electronic): 2167-8359
                Publication date (Electronic): 23 March 2020
                Publication date Collection: 2020
                Volume: 8
                Electronic Location Identifier: e8702
                Affiliations
                [1 ]Department of Histology and Embryology, Nanjing Medical University , Nanjing, China
                [2 ]Animal Core Facility, Nanjing Medical University , Nanjing, Jiangsu, China
                Article
                Publisher ID: 8702
                DOI: 10.7717/peerj.8702
                PMC ID: 7098389
                PubMed ID: 32231871
                SO-VID: 808fb471-56e8-4112-b561-ec27233a181e
                Copyright © ©2020 Wang et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                Date received : 24 December 2019
                Date accepted : 6 February 2020
                Funding
                Funded by: National Key R&D Program
                Award ID: 2017YFA0103803
                Award ID: 2016YFA0500903
                Award ID: 2016YFA0503300
                Funded by: National Natural Science Foundation of China
                Award ID: 31571538
                Award ID: 31771651
                Award ID: 31890784
                Award ID: 31701300
                Funded by: Natural Science Foundation of Jiangsu Province
                Award ID: BK20190081
                This work was supported by the National Key R&D Program (2017YFA0103803, 2016YFA0500903, 2016YFA0503300), the National Natural Science Foundation of China (31571538, 31771651, 31890784 and 31701300), and Natural Science Foundation of Jiangsu Province (Grants No. BK20190081). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Biochemistry
                Subject: Andrology

                Keywords: hspa1l,spermatogenesis,male infertility,gene knockout
                Data availability:
                Keywords: hspa1l, spermatogenesis, male infertility, gene knockout

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