{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n INPP5B is an inositol polyphosphate 5‐phosphatase highly homologous to OCRL1 yet with distinct cellular functions and localization. Although both enzymes share similar substrate specificity and domain organization, INPP5B lacks the clathrin and AP2–binding capacity that is characteristic of OCRL1, indicating that it is not recruited to late‐stage clathrin‐coated pits and does not participate in ruffle‐mediated membrane remodeling in the same manner as OCRL1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In contrast, recent work has revealed that INPP5B localizes to components of the early secretory pathway – including the Golgi apparatus and the ER–Golgi intermediate compartment (ERGIC) – where it binds specific RAB proteins; this targeting is critical for its role in mediating retrograde ERGIC‐to‐ER transport, a function that is distinct from the endocytic activities of OCRL1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, INPP5B interacts with the endocytic adaptor proteins IPIP27A and IPIP27B (Ses1/2), which are required for proper receptor recycling from endosomes and the trans‐Golgi network."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, during pathogen invasion, both OCRL1 and INPP5B are transiently recruited to PI(4,5)P2‐rich prevacuolar compartments to aid in membrane scission processes, thereby highlighting a role for INPP5B in regulating membrane dynamics during endocytosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Importantly, studies in animal models have demonstrated that INPP5B has specialized functions in non‐endocytic pathways. For example, in the testis, deficiency of INPP5B disrupts the formation and maintenance of intercellular junctions in Sertoli cells, leading to the accumulation of aberrant endosome‐like structures and premature release of developing germ cells, thereby implicating INPP5B in the regulation of cell adhesion during spermatogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Similarly, analyses of sperm from Inpp5b knockout mice have shown that loss of INPP5B compromises sperm–egg binding and fusion, which correlates with reduced male fertility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, comparative work indicates that differences in transcription, splicing, and primary sequence between mouse Inpp5b and human INPP5B may underlie species‐specific compensation for OCRL1 deficiency, although variations in INPP5B levels do not appear to account for the phenotypic heterogeneity observed in Lowe syndrome versus Dent‐2 disease"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these findings delineate a multifaceted role for INPP5B in regulating phosphoinositide metabolism within the early secretory pathway and in specific membrane trafficking and cell adhesion processes that are essential for normal reproductive function.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yuxin Mao, Daniel M Balkin, Roberto Zoncu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2009.155"}], "href": "https://doi.org/10.1038/emboj.2009.155"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19536138"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19536138"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Brian G Coon, Debarati Mukherjee, Claudia B Hanna, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase."}]}, {"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/ddp407"}], "href": "https://doi.org/10.1093/hmg/ddp407"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19700499"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19700499"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Catrin Williams, Rawshan Choudhury, Eddie McKenzie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.014423"}], "href": "https://doi.org/10.1242/jcs.014423"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17956944"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17956944"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Christopher J Noakes, Grace Lee, Martin Lowe "}, {"type": "b", "children": [{"type": "t", "text": "The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway."}]}, {"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.E10-08-0730"}], "href": "https://doi.org/10.1091/mbc.E10-08-0730"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21233288"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21233288"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Helen Sarantis, Daniel M Balkin, Pietro De Camilli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Yersinia entry into host cells requires Rab5-dependent dephosphorylation of PI(4,5)P₂ and membrane scission."}]}, {"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.2012.01.010"}], "href": "https://doi.org/10.1016/j.chom.2012.01.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22341461"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22341461"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Elina Hellsten, David J Bernard, Jennie W Owens, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sertoli cell vacuolization and abnormal germ cell adhesion in mice deficient in an inositol polyphosphate 5-phosphatase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Reprod (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1095/biolreprod66.5.1522"}], "href": "https://doi.org/10.1095/biolreprod66.5.1522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11967219"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11967219"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Matthew R Marcello, Janice P Evans "}, {"type": "b", "children": [{"type": "t", "text": "Multivariate analysis of male reproductive function in Inpp5b-/- mice reveals heterogeneity in defects in fertility, sperm-egg membrane interaction and proteolytic cleavage of sperm ADAMs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Hum Reprod (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molehr/gaq029"}], "href": "https://doi.org/10.1093/molehr/gaq029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20403911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20403911"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Susan P Bothwell, Leslie W Farber, Adam Hoagland, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Species-specific difference in expression and splice-site choice in Inpp5b, an inositol polyphosphate 5-phosphatase paralogous to the enzyme deficient in Lowe Syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mamm Genome (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00335-010-9281-7"}], "href": "https://doi.org/10.1007/s00335-010-9281-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20872266"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20872266"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Rodrick Montjean, Rifdat Aoidi, Pierrette Desbois, et al. "}, {"type": "b", "children": [{"type": "t", "text": "OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu514"}], "href": "https://doi.org/10.1093/hmg/ddu514"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25305077"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25305077"}]}]}]}