{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DNAJB11, which encodes an endoplasmic reticulum–resident Hsp40 co‐chaperone (also known as ERdj3), is emerging as a central regulator of ER proteostasis. By partnering with the major ER chaperone BiP, DNAJB11 facilitates the proper folding, assembly, and quality control of nascent secretory and membrane proteins. This cooperative activity not only promotes efficient protein trafficking and degradation of misfolded clients but also helps prevent protein aggregation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, DNAJB11 is dynamically regulated during endoplasmic reticulum stress. Activation of the unfolded protein response leads to its up‐regulation and even secretion into the extracellular space, where it extends its chaperoning function to maintain extracellular proteostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, DNAJB11 is implicated in the selective targeting and processing of critical substrates. For instance, it can transiently associate with immunoglobulin heavy chains to assist in their folding and eventual degradation when misfolding occurs"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and it is directly engaged by pathogenic effectors such as bacterial E3 ubiquitin ligases or viral proteins, influencing both host protein quality control and cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Importantly, genetic studies have shown that loss‐of‐function mutations in DNAJB11 are associated with forms of cystic kidney disease—a hybrid phenotype of autosomal dominant polycystic kidney disease and tubulointerstitial kidney disease—underscoring its critical role in the maturation and trafficking of essential proteins such as polycystin‐1 and uromodulin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies demonstrate that DNAJB11 is pivotal for maintaining ER and extracellular proteostasis by modulating BiP activity, regulating protein folding and quality control, and thereby influencing cell survival and disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Emilie Cornec-Le Gall, Rory J Olson, Whitney Besse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2018.03.013"}], "href": "https://doi.org/10.1016/j.ajhg.2018.03.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29706351"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29706351"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Christiane Bies, Robert Blum, Johanna Dudek, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Co-chaperone Specificity in Gating of the Polypeptide Conducting Channel in the Membrane of the Human Endoplasmic Reticulum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.636639"}], "href": "https://doi.org/10.1074/jbc.M115.636639"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26085089"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26085089"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Joseph C Genereux, Song Qu, Minghai Zhou, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The endoplasmic reticulum HSP40 co-chaperone ERdj3/DNAJB11 assembles and functions as a tetramer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.201695616"}], "href": "https://doi.org/10.15252/embj.201695616"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28655754"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28655754"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ying Shen, Linda M Hendershot "}, {"type": "b", "children": [{"type": "t", "text": "ERdj3, a stress-inducible endoplasmic reticulum DnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e04-05-0434"}], "href": "https://doi.org/10.1091/mbc.e04-05-0434"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15525676"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15525676"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Joaquín Bernal-Bayard, Elena Cardenal-Muñoz, Francisco Ramos-Morales "}, {"type": "b", "children": [{"type": "t", "text": "The Salmonella type III secretion effector, salmonella leucine-rich repeat protein (SlrP), targets the human chaperone ERdj3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.100669"}], "href": "https://doi.org/10.1074/jbc.M110.100669"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20335166"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20335166"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "K W Wen, B Damania "}, {"type": "b", "children": [{"type": "t", "text": "Hsp90 and Hsp40/Erdj3 are required for the expression and anti-apoptotic function of KSHV K1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2010.124"}], "href": "https://doi.org/10.1038/onc.2010.124"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20418907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20418907"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Vinh T Huynh, Marie-Pierre Audrézet, John A Sayer, et al. 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