{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DNAJB12 is an endoplasmic reticulum–anchored Hsp40 (DNAJ) co‐chaperone that plays a central role in protein quality control at the ER membrane. By recruiting cytosolic Hsc70/Hsp70 via its cytosolically oriented J‐domain, DNAJB12 facilitates the triage of nascent and misfolded transmembrane proteins, most notably the cystic fibrosis transmembrane conductance regulator (CFTR), directing them toward proper folding or degradation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Elevated levels of DNAJB12 enhance the association of Hsc70 with ER‐resident forms of CFTR and its mutant variants, thereby accelerating their clearance via the ubiquitin–proteasome system; conversely, depletion of DNAJB12 improves the folding efficiency of these membrane proteins (1,2). \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its canonical role in ER‐associated degradation (ERAD), DNAJB12 contributes to the decision-making process that partitions misfolded proteins between degradation and alternative clearance pathways. For instance, in the context of misfolded CFTR mutants that are resistant to ERAD, DNAJB12 helps divert substrates into selective autophagy pathways, underscoring its function as a conformation-specific triage factor."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, during severe ER stress, DNAJB12 itself becomes a target for proteasomal degradation—a process linked to the regulation of apoptotic mediators such as BOK—highlighting its role in stress‐induced proteostasis and cell fate determination."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its involvement in protein folding and degradation, DNAJB12 also participates in the cellular response to viral infection. It collaborates with Hsc70 to remodel ER membranes and facilitate the ER‐to‐cytosol transport of viral components, as seen with polyomavirus and insect‐transmitted viral tubule assembly."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In parallel, the over‐expression of full-length DNAJB12 (in conjunction with its homolog DNAJB14) can drive the formation of unique intranuclear membranous structures, termed DJANGOS, which further underscores the multifaceted roles of this co-chaperone in cellular membrane dynamics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies establish DNAJB12 as a pivotal ER-resident co-chaperone that integrates folding and degradation signals to maintain proteostasis, modulating the fate of both misfolded membrane proteins and stress‐orchestrated apoptotic signaling, as well as impacting viral entry processes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Diane E Grove, Chun-Yang Fan, Hong Yu Ren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The endoplasmic reticulum-associated Hsp40 DNAJB12 and Hsc70 cooperate to facilitate RMA1 E3-dependent degradation of nascent CFTRDeltaF508."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E10-09-0760"}], "href": "https://doi.org/10.1091/mbc.E10-09-0760"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21148293"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21148293"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yo-hei Yamamoto, Taiji Kimura, Shuku Momohara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel ER J-protein DNAJB12 accelerates ER-associated degradation of membrane proteins including CFTR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Struct Funct (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1247/csf.10023"}], "href": "https://doi.org/10.1247/csf.10023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21150129"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21150129"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Pattarawut Sopha, Hiroshi Kadokura, Yo-hei Yamamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel mammalian ER-located J-protein, DNAJB14, can accelerate ERAD of misfolded membrane proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Struct Funct (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1247/csf.12017"}], "href": "https://doi.org/10.1247/csf.12017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23018488"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23018488"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Lihua He, Andrew S Kennedy, Scott Houck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNAJB12 and Hsp70 triage arrested intermediates of N1303K-CFTR for endoplasmic reticulum-associated autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E20-11-0688"}], "href": "https://doi.org/10.1091/mbc.E20-11-0688"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33534640"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33534640"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Pattarawut Sopha, Hong Yu Ren, Diane E Grove, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endoplasmic reticulum stress-induced degradation of DNAJB12 stimulates BOK accumulation and primes cancer cells for apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M117.785113"}], "href": "https://doi.org/10.1074/jbc.M117.785113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28536268"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28536268"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Qifu Liang, Jiajia Wan, Huan Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A plant reovirus hijacks the DNAJB12-Hsc70 chaperone complex to promote viral spread in its planthopper vector."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Plant Pathol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/mpp.13152"}], "href": "https://doi.org/10.1111/mpp.13152"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34668642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34668642"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Christopher Paul Walczak, Madhu Sudhan Ravindran, Takamasa Inoue, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A cytosolic chaperone complexes with dynamic membrane J-proteins and mobilizes a nonenveloped virus out of the endoplasmic reticulum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Pathog (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.ppat.1004007"}], "href": "https://doi.org/10.1371/journal.ppat.1004007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24675744"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24675744"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Edward C Goodwin, Nasim Motamedi, Alex Lipovsky, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of DNAJB12 or DNAJB14 causes coordinate invasion of the nucleus by membranes associated with a novel nuclear pore structure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0094322"}], "href": "https://doi.org/10.1371/journal.pone.0094322"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24732912"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24732912"}]}]}]}