{"type": "root", "children": [{"type": "t", "text": "<div>\n "}, {"type": "p", "children": [{"type": "t", "text": "\n HSPA4L, a member of the HSP110 family, functions as a molecular chaperone that supports protein homeostasis under both basal and stress conditions and plays multifaceted roles in diverse biological processes. In the reproductive system, HSPA4L is highly expressed in germ cells, particularly in the testis, where it is essential for normal spermatogenesis and sperm maturation. Gene targeting studies in mice have revealed that loss of HSPA4L results in increased apoptosis of developing germ cells, reduced sperm count and motility, and an enhanced sensitivity to osmotic stress—underscoring its importance in male fertility and cellular osmotolerance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its roles in reproduction, HSPA4L has been implicated in cancer biology. In nasopharyngeal carcinoma, for example, HSPA4L is overexpressed and is negatively regulated by the tumor‐suppressive microRNA miR-497. Silencing of HSPA4L in these tumor cells suppresses proliferation and migration while inducing apoptosis, suggesting that aberrant HSPA4L function may contribute to tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n HSPA4L also contributes to embryonic development and proteome quality control. In murine models, combined deficiency of HSPA4L and its closely related cochaperone HSPA4 disrupts lung maturation by impairing the clearance of ubiquitinated proteins, which results in mesenchymal hypercellularity and defective differentiation of pneumocytes—a finding that highlights the crucial role of these chaperones in tissue development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, HSPA4L is dynamically regulated in response to cellular stress. In multiple myeloma cells, exposure to proteasome inhibitors triggers HSPA4L upregulation, and its knockdown increases sensitivity to such treatments, linking its function to cellular survival mechanisms under proteotoxic conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In evolutionary divergent models, such as rainbow trout, HSPA4L is targeted by stress-responsive microRNAs during heat exposure, indicating a conserved role in the cellular heat shock response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n At the molecular level, HSPA4L acts as a “holdase” chaperone that prevents protein aggregation and facilitates the refolding of heat-inactivated proteins. Its C-terminal domain appears to function in a manner analogous to proteasome activators, highlighting its versatility in reactivating misfolded substrates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies illustrate that HSPA4L plays critical roles in maintaining protein quality control, supporting fertility, guiding proper tissue development, modulating cellular stress responses, and influencing cancer cell phenotypes.\n "}]}, {"type": "t", "text": "\n</div>"}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Torsten Held, Ilona Paprotta, Janchiv Khulan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hspa4l-deficient mice display increased incidence of male infertility and hydronephrosis development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01332-06"}], "href": "https://doi.org/10.1128/MCB.01332-06"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16923965"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16923965"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "XueXia Liu, Xiong Wang, FuJun Liu "}, {"type": "b", "children": [{"type": "t", "text": "Decreased expression of heat shock protein A4L in spermatozoa is positively related to poor human sperm quality."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Reprod Dev (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mrd.23113"}], "href": "https://doi.org/10.1002/mrd.23113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30637842"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30637842"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kenta Nagahori, Shuichi Hirai, Naoyuki Hatayama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heat shock protein A4L is a potent autoantigen for testicular autoimmunity in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Reprod Immunol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jri.2021.103318"}], "href": "https://doi.org/10.1016/j.jri.2021.103318"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33894646"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33894646"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Shumin Wang, Yingxi Mo, Kaoru Midorikawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The potent tumor suppressor miR-497 inhibits cancer phenotypes in nasopharyngeal carcinoma by targeting ANLN and HSPA4L."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.5651"}], "href": "https://doi.org/10.18632/oncotarget.5651"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26486082"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26486082"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Belal A Mohamed, Amal Z Barakat, Torsten Held, et al. 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