{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nA series of recent studies have delineated the critical roles of endoplasmic reticulum (ER)‐resident ubiquitin ligases and their associated factors in maintaining protein quality control, regulating lipid metabolism, and coordinating immune and cellular stress responses. For example, one study showed that mPNGase forms a complex with mAMFR to couple retrotranslocation, ubiquitination, and deglycosylation of misfolded glycoproteins ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]. In another investigation, the involvement of gp78 as the autocrine motility factor receptor was demonstrated in leukemic differentiation, establishing its dual roles in cell motility and proliferation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "]. Moreover, ER stress was found to stabilize gp78 and enhance ER‐associated degradation (ERAD) ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "], while additional work showed that gp78 promotes metastasis by targeting the metastasis suppressor KAI1 for degradation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]. The degradation of misfolded proteins such as the CFTR mutant CFTRΔF508, regulated by gp78’s ubiquitin ligase activity, further underscores its central role in ER quality control ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]. In the context of neurodegeneration, gp78 has been implicated in the ubiquitination and degradation of proteins like SOD1 and ataxin‐3 ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "], and its role in modulating cell proliferation was confirmed using mammary gland transgenic models ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "]. Other studies have established correlations between AMFR expression and hippocampal function ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "] and have revealed that post‐translational modifications such as palmitoylation can regulate the ER distribution and activity of gp78 ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]. The regulation of lipid homeostasis in liver is also tightly linked to gp78 activity, as liver‐specific knockout models show altered degradation of the rate‐limiting enzyme HMG-CoA reductase, along with changes in Insig proteins and downstream effects on metabolism ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "]. In addition, studies have identified the involvement of TRC8 in HMG-CoA reductase degradation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "] and have shown that gp78 mediates the degradation of prion protein PrP ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "]. Further extending the scope of gp78 function, STING-mediated innate immune signaling was found to depend on AMFR and INSIG1, and the coordinated actions of RNF145 with gp78 have been implicated in sterol-accelerated HMG-CoA reductase degradation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "], while the dynamic regulation of gp78 by calmodulin was shown to influence proteostasis and ER–mitochondria interactions ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNotably, while these studies collectively advance our understanding of ER-associated degradation, lipid regulation, immune signaling, and cellular stress responses, none of them provide any insights into the function of SNORA63. SNORA63—a small nucleolar RNA typically involved in guiding rRNA modification—remains unaddressed within this body of work. Therefore, its potential roles or connections with the aforementioned pathways are yet to be determined and warrant further dedicated investigation.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Guangtao Li, Gang Zhao, Xiaoke Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The AAA ATPase p97 links peptide N-glycanase to the endoplasmic reticulum-associated E3 ligase autocrine motility factor receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0602747103"}], "href": "https://doi.org/10.1073/pnas.0602747103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16709668"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16709668"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Arayo Haga, Sachiko Komazaki, Tatsuyoshi Funasaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AMF/G6PI induces differentiation of leukemic cells via an unknown receptor that differs from gp78."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leuk Lymphoma (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/10428190600773263"}], "href": "https://doi.org/10.1080/10428190600773263"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17071500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17071500"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yuxian Shen, Petek Ballar, Andria Apostolou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ER stress differentially regulates the stabilities of ERAD ubiquitin ligases and their substrates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2006.11.121"}], "href": "https://doi.org/10.1016/j.bbrc.2006.11.121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17157811"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17157811"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yien Che Tsai, Arnulfo Mendoza, Jennifer M Mariano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm1686"}], "href": "https://doi.org/10.1038/nm1686"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18037895"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18037895"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Daisuke Morito, Kazuyoshi Hirao, Yukako Oda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gp78 cooperates with RMA1 in endoplasmic reticulum-associated degradation of CFTRDeltaF508."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e07-06-0601"}], "href": "https://doi.org/10.1091/mbc.e07-06-0601"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18216283"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18216283"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Zheng Ying, Hongfeng Wang, Huadong Fan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddp380"}], "href": "https://doi.org/10.1093/hmg/ddp380"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19661182"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19661182"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Bharat Joshi, Lei Li, Ivan R Nabi "}, {"type": "b", "children": [{"type": "t", "text": "A role for KAI1 in promotion of cell proliferation and mammary gland hyperplasia by the gp78 ubiquitin ligase."}]}, {"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.M109.074344"}], "href": "https://doi.org/10.1074/jbc.M109.074344"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20089858"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20089858"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yong Yang, Xiao-Rui Cheng, Gui-Rong Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autocrine motility factor receptor is involved in the process of learning and memory in the central nervous system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Behav Brain Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbr.2012.01.043"}], "href": "https://doi.org/10.1016/j.bbr.2012.01.043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22313999"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22313999"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Maria Fairbank, Kun Huang, Alaa El-Husseini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RING finger palmitoylation of the endoplasmic reticulum Gp78 E3 ubiquitin ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2012.06.011"}], "href": "https://doi.org/10.1016/j.febslet.2012.06.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22728137"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22728137"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Tong-Fei Liu, Jing-Jie Tang, Pei-Shan Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2012.06.014"}], "href": "https://doi.org/10.1016/j.cmet.2012.06.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22863805"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22863805"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Tianpeng Zhang, Dhong Hyo Kho, Ying Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0118448"}], "href": "https://doi.org/10.1371/journal.pone.0118448"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25789613"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25789613"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Jie Li, Guocai Liu, Feng Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of glycoprotein 78 and cidec in hepatic steatosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2017.6834"}], "href": "https://doi.org/10.3892/mmr.2017.6834"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28656280"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28656280"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yien Che Tsai, Gil S Leichner, Margaret M P Pearce, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E12-08-0631"}], "href": "https://doi.org/10.1091/mbc.E12-08-0631"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23087214"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23087214"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Jia Shao, Vitnary Choe, Haili Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitin ligase gp78 targets unglycosylated prion protein PrP for ubiquitylation and degradation."}]}, {"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.0092290"}], "href": "https://doi.org/10.1371/journal.pone.0092290"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24714645"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24714645"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Qiang Wang, Xing Liu, Ye Cui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunity (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.immuni.2014.11.011"}], "href": "https://doi.org/10.1016/j.immuni.2014.11.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25526307"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25526307"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Sam A Menzies, Norbert Volkmar, Dick Jh van den Boomen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The sterol-responsive RNF145 E3 ubiquitin ligase mediates the degradation of HMG-CoA reductase together with gp78 and Hrd1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.40009"}], "href": "https://doi.org/10.7554/eLife.40009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30543180"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30543180"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Rukmini Mukherjee, Anshu Bhattacharya, Abhishek Sau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calmodulin regulates MGRN1-GP78 interaction mediated ubiquitin proteasomal degradation system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.201701413RRR"}], "href": "https://doi.org/10.1096/fj.201701413RRR"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30230921"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30230921"}]}]}]}