{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HSPA8 (heat shock protein family A [Hsp70] member 8), the constitutively expressed form of Hsp70, plays multifaceted roles in maintaining cellular proteostasis. In one capacity, HSPA8 facilitates chaperone‐mediated autophagy (CMA) by recognizing and binding to newly synthesized or aberrantly modified proteins—such as acetylated PKM2—and escorting them to lysosomes for degradation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, HSPA8 cooperates with the ubiquitin ligase CHIP to target misfolded or posttranslationally modified proteins for proteasomal degradation. This mechanism is exemplified by its role in binding phosphorylated tau to promote CHIP‐mediated ubiquitination"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", in facilitating the turnover of both mutant and wild‐type p53"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", and in assisting the quality control of misfolded CFTR variants."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n HSPA8 is also a critical component of multi‐protein complexes that promote selective autophagic clearance in neurodegenerative settings. For instance, within the HspB8/Bag3/HSPA8/CHIP complex, it aids in the autophagic removal of aggregation‐prone proteins such as mutant superoxide dismutase 1 (SOD1) and truncated TDP‐43, thereby reducing toxic buildup in affected neurons."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Beyond its roles in protein degradation, HSPA8 contributes to antigen processing; its interaction with Lamp‐2A facilitates the presentation of cytoplasmic peptides by MHC class II molecules in antigen‐presenting cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, regulation of HSPA8 localization is vital for proper cell cycle control in hematopoietic stem cells, where its cytoplasmic distribution (in association with cyclin D1) is modulated by factors such as p57 and p27 to maintain HSC quiescence."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, HSPA8 is integral to chaperone‐assisted selective autophagy (CASA), a specialized pathway that, together with other chaperones and cofactors, ensures cytoskeletal integrity and effective mechanotransduction under conditions of mechanical tension."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore the diverse and critical functions of HSPA8 in protein quality control, regulated protein degradation, antigen presentation, and the maintenance of cellular homeostasis in both normal physiology and disease.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lei Lv, Dong Li, Di Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2011.04.025"}], "href": "https://doi.org/10.1016/j.molcel.2011.04.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21700219"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21700219"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Urmi Bandyopadhyay, Susmita Kaushik, Lyuba Varticovski, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.02070-07"}], "href": "https://doi.org/10.1128/MCB.02070-07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18644871"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18644871"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hideki Shimura, Daniel Schwartz, Steven P Gygi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M305838200"}], "href": "https://doi.org/10.1074/jbc.M305838200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14612456"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14612456"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Claudia Esser, Martin Scheffner, Jörg Höhfeld "}, {"type": "b", "children": [{"type": "t", "text": "The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M501574200"}], "href": "https://doi.org/10.1074/jbc.M501574200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15911628"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15911628"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "J Michael Younger, Liling Chen, Hong-Yu Ren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2006.06.041"}], "href": "https://doi.org/10.1016/j.cell.2006.06.041"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16901789"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16901789"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Valeria Crippa, Daniela Sau, Paola Rusmini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddq257"}], "href": "https://doi.org/10.1093/hmg/ddq257"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20570967"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20570967"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Delu Zhou, Ping Li, Yinling Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lamp-2a facilitates MHC class II presentation of cytoplasmic antigens."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunity (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.immuni.2005.03.009"}], "href": "https://doi.org/10.1016/j.immuni.2005.03.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15894275"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15894275"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Peng Zou, Hiroki Yoshihara, Kentaro Hosokawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Stem Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stem.2011.07.003"}], "href": "https://doi.org/10.1016/j.stem.2011.07.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21885020"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21885020"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Anna Ulbricht, Felix J Eppler, Victor E Tapia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cub.2013.01.064"}], "href": "https://doi.org/10.1016/j.cub.2013.01.064"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23434281"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23434281"}]}]}]}