{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n LRSAM1 is a multifunctional RING‐type E3 ubiquitin ligase that plays critical roles in both host defense and neural homeostasis. In the context of antibacterial autophagy, LRSAM1 facilitates the ubiquitin coating of invading pathogens—such as Salmonella—thereby promoting their recognition by cellular cargo receptors and subsequent degradation via the autophagy machinery (<!-- link 1 -->"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", <!-- link 2 -->"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", <!-- link 3 -->."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " At the molecular level, LRSAM1 exhibits regulated self‐association and domain interplay—particularly involving its leucine‐rich repeat and RING finger regions—that is essential for efficient ubiquitin chain formation on its substrates such as TSG101, a key component of endosomal sorting processes. This regulation of ubiquitination activity underpins its role in protein quality control and intracellular sorting."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, genetic studies have implicated LRSAM1 in neuronal integrity. Mutations in LRSAM1 have been linked to both dominant and recessive forms of axonal Charcot–Marie–Tooth (CMT) neuropathies, where impaired LRSAM1 function is associated with axonal degeneration and sensory–motor deficits (<!-- link 4 -->"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", <!-- link 5 -->"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", <!-- link 6 -->."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, regulation of LRSAM1 expression by microRNAs, such as miR‐431–5p, indicates that its modulation can impact neuronal progenitor cell proliferation, providing further evidence for its role in neural development and disease (<!-- link 8 -->."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Overall, LRSAM1 is emerging as a key regulatory node at the intersection of innate immunity and nervous system maintenance. Through its ubiquitin ligase activity—modulated by domain interactions that ensure precise substrate targeting and autoubiquitination—it not only orchestrates the clearance of intracellular pathogens but also maintains cellular proteostasis and neuronal function (<!-- link 7 -->"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", <!-- link 9 -->."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alan Huett, Robert J Heath, Jakob Begun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Host Microbe (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chom.2012.10.019"}], "href": "https://doi.org/10.1016/j.chom.2012.10.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23245322"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23245322"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Aylwin C Y Ng, Jason M Eisenberg, Robert J W Heath, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1000093107"}], "href": "https://doi.org/10.1073/pnas.1000093107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20616063"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20616063"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Deepak Chhangani, Arun Upadhyay, Ayeman Amanullah, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitin ligase ITCH recruitment suppresses the aggregation and cellular toxicity of cytoplasmic misfolded proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep05077"}], "href": "https://doi.org/10.1038/srep05077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24865853"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24865853"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Celeste Montecchiani, Lucia Pedace, Temistocle Lo Giudice, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awv320"}], "href": "https://doi.org/10.1093/brain/awv320"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26556829"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26556829"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Guohua Zhao, Jie Song, Mi Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel mutation of LRSAM1 in a Chinese family with Charcot-Marie-Tooth disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Peripher Nerv Syst (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jns.12247"}], "href": "https://doi.org/10.1111/jns.12247"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29341362"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29341362"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Alessia Peretti, Maud Perie, Didier Vincent, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41431-019-0403-8"}], "href": "https://doi.org/10.1038/s41431-019-0403-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30996334"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30996334"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Bo Hu, Lei Cao, Xiao-Ye Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of microRNA-431-5p promotes enteric neural crest cell proliferation via targeting LRSAM1 in Hirschsprung's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Growth Differ (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/dgd.12606"}], "href": "https://doi.org/10.1111/dgd.12606"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31037734"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31037734"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Weixiang Bian, Yanmin Guo, Yuan Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The self-association and activity regulation of LRSAM1 E3 ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2017.02.026"}], "href": "https://doi.org/10.1016/j.bbrc.2017.02.026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28189685"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28189685"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ribhav Mishra, Arun Upadhyay, Vijay Kumar Prajapati, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LRSAM1 E3 ubiquitin ligase: molecular neurobiological perspectives linked with brain diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-019-03055-y"}], "href": "https://doi.org/10.1007/s00018-019-03055-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30826859"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30826859"}]}]}]}