PSIP1

PSIP1 has not been clearly linked to a specific cellular mechanism. The term LEDGF/p75 (Lens epithelium-derived growth factor) has entered common usage based on the initial characterization of PSIP1, however this is a misnomer, as the protein is present in most tissues and has no direct role in the development of lens epithelium. LEDGF/p75, a transcription coactivator, gained prominence as a host factor that assists HIV integration{{cite journal | vauthors = Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z | title = HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells | journal = J. Biol. Chem. | volume = 278 | issue = 1 | pages = 372–81 | date = January 2003 | pmid = 12407101 | doi = 10.1074/jbc.M209278200 | doi-access = free }} and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels.{{cite journal | vauthors = Vandekerckhove L, Christ F, Van Maele B, De Rijck J, Gijsbers R, Van den Haute C, Witvrouw M, Debyser Z | title = Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus | journal = J. Virol. | volume = 80 | issue = 4 | pages = 1886–96 | date = February 2006 | pmid = 16439544 | pmc = 1367129 | doi = 10.1128/JVI.80.4.1886-1896.2006 }}{{cite journal | vauthors = Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A | title = LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration | journal = Genes Dev. | volume = 21 | issue = 14 | pages = 1767–78 | date = July 2007 | pmid = 17639082 | pmc = 1920171 | doi = 10.1101/gad.1565107 }}{{cite journal | vauthors = Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, Teo W, Poeschla EM | title = An essential role for LEDGF/p75 in HIV integration | journal = Science | volume = 314 | issue = 5798 | pages = 461–4 | date = October 2006 | pmid = 16959972 | doi = 10.1126/science.1132319 | bibcode = 2006Sci...314..461L | s2cid = 24756699 }} The interaction between HIV integrase and human LEDGF/p75 is a promising target for anti-HIV drug discovery.{{cite journal | vauthors = Christ F, Voet A, Marchand A, Nicolet S, Desimmie BA, Marchand D, Bardiot D, Van der Veken NJ, Van Remoortel B, Strelkov SV, De Maeyer M, Chaltin P, Debyser Z | title = Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication | journal = Nat. Chem. Biol. | volume = 6 | issue = 6 | pages = 442–8 | date = June 2010 | pmid = 20473303 | doi = 10.1038/nchembio.370 | s2cid = 37421436 }} LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression.{{Cite journal|last1=Pradeepa|first1=Madapura M.|last2=Grimes|first2=Graeme R.|last3=Taylor|first3=Gillian C. A.|last4=Sutherland|first4=Heidi G.|last5=Bickmore|first5=Wendy A.|date=2014-08-18|title=Psip1/Ledgf p75 restrains Hox gene expression by recruiting both trithorax and polycomb group proteins|journal=Nucleic Acids Research|volume=42|issue=14|pages=9021–9032|doi=10.1093/nar/gku647|issn=0305-1048|pmc=4132756|pmid=25056311}} LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing,{{Cite journal|last1=Pradeepa|first1=Madapura M.|last2=Sutherland|first2=Heidi G.|last3=Ule|first3=Jernej|last4=Grimes|first4=Graeme R.|last5=Bickmore|first5=Wendy A.|date=2012-05-17|title=Psip1/Ledgf p52 Binds Methylated Histone H3K36 and Splicing Factors and Contributes to the Regulation of Alternative Splicing|journal=PLOS Genetics|volume=8|issue=5|pages=e1002717|doi=10.1371/journal.pgen.1002717|issn=1553-7404|pmc=3355077|pmid=22615581 |doi-access=free }} also regulates HOTTIP lncRNA, which is shown to regulate HOX genes in cis.{{Cite journal|last1=Pradeepa|first1=Madapura M.|last2=McKenna|first2=Fionnuala|last3=Taylor|first3=Gillian C. A.|last4=Bengani|first4=Hemant|last5=Grimes|first5=Graeme R.|last6=Wood|first6=Andrew J.|last7=Bhatia|first7=Shipra|last8=Bickmore|first8=Wendy A.|date=2017-04-06|title=Psip1/p52 regulates posterior Hoxa genes through activation of lncRNA Hottip|journal=PLOS Genetics|volume=13|issue=4|pages=e1006677|doi=10.1371/journal.pgen.1006677|issn=1553-7404|pmc=5383017|pmid=28384324 |doi-access=free }}

LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.{{cite book|author-link3=Eric Poeschla | vauthors = Llano M, Morrison J, Poeschla EM | chapter = Virological and Cellular Roles of the Transcriptional Coactivator LEDGF/P75 | title = HIV Interactions with Host Cell Proteins | journal = Curr. Top. Microbiol. Immunol. | volume = 339 | pages = 125–46 | year = 2009 | pmid = 20012527 | pmc = 3093762 | doi = 10.1007/978-3-642-02175-6_7 | series = Current Topics in Microbiology and Immunology | isbn = 978-3-642-02174-9 }} The N-terminal portion of the protein consists of a PWWP domain, a nuclear localization sequence, and two copies of the AT-hook DNA binding motif. The C-terminal portion of LEDGF/p75 contains a structure termed the integrase-binding domain,{{cite journal | vauthors = Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A | title = Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75 | journal = Nat. Struct. Mol. Biol. | volume = 12 | issue = 6 | pages = 526–32 | date = June 2005 | pmid = 15895093 | doi = 10.1038/nsmb937| s2cid = 20898124 }} which interacts with lentiviral integrase proteins as well as numerous cellular proteins. The N-terminal portion interacts strongly with chromatin, making LEDGF/p75 a constitutively nuclear protein. An isoform of the protein, LEDGF/p52, is produced by alternative splicing. LEDGF/p52 shares the N-terminal 325 amino acids of LEDGF/p75 but lacks the integrase-binding domain.

PSIP1 has been shown to interact with the proteins ASF/SF2, JPO2, Cdc7-Dbf4, and POGZ as well as the menin/MLL protein complex.{{cite journal | vauthors = Ge H, Si Y, Wolffe AP | title = A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2 | journal = Mol. Cell | volume = 2 | issue = 6 | pages = 751–9 | date = December 1998 | pmid = 9885563 | doi = 10.1016/S1097-2765(00)80290-7 | doi-access = free }}{{cite journal | vauthors = Hughes S, Jenkins V, Dar MJ, Engelman A, Cherepanov P | title = Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity | journal = J. Biol. Chem. | volume = 285 | issue = 1 | pages = 541–54 | date = January 2010 | pmid = 19864417 | pmc = 2804203 | doi = 10.1074/jbc.M109.036491 | doi-access = free }}

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• {{cite journal | vauthors = Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A | title = LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration | journal = Genes Dev. | volume = 21 | issue = 14 | pages = 1767–78 | date = July 2007 | pmid = 17639082 | pmc = 1920171 | doi = 10.1101/gad.1565107 }}
• {{cite journal | vauthors = Van Maele B, Debyser Z | title = HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins | journal = AIDS Rev | volume = 7 | issue = 1 | pages = 26–43 | year = 2005 | pmid = 15875659 }}
• {{cite journal | vauthors = Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z | title = Cellular co-factors of HIV-1 integration | journal = Trends Biochem. Sci. | volume = 31 | issue = 2 | pages = 98–105 | year = 2006 | pmid = 16403635 | doi = 10.1016/j.tibs.2005.12.002 }}
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• {{cite journal | vauthors = Ge H, Si Y, Roeder RG | title = Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation | journal = EMBO J. | volume = 17 | issue = 22 | pages = 6723–9 | year = 1998 | pmid = 9822615 | pmc = 1171017 | doi = 10.1093/emboj/17.22.6723 }}
• {{cite journal | vauthors = Ge H, Si Y, Wolffe AP | title = A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2 | journal = Mol. Cell | volume = 2 | issue = 6 | pages = 751–9 | year = 1998 | pmid = 9885563 | doi = 10.1016/S1097-2765(00)80290-7 | doi-access = free }}
• {{cite journal | vauthors = Singh DP, Ohguro N, Kikuchi T, Sueno T, Reddy VN, Yuge K, Chylack LT, Shinohara T | title = Lens epithelium-derived growth factor: effects on growth and survival of lens epithelial cells, keratinocytes, and fibroblasts | journal = Biochem. Biophys. Res. Commun. | volume = 267 | issue = 1 | pages = 373–81 | year = 2000 | pmid = 10623627 | doi = 10.1006/bbrc.1999.1979 }}
• {{cite journal | vauthors = Singh DP, Kimura A, Chylack LT, Shinohara T | title = Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing | journal = Gene | volume = 242 | issue = 1–2 | pages = 265–73 | year = 2000 | pmid = 10721720 | doi = 10.1016/S0378-1119(99)00506-5 }}
• {{cite journal | vauthors = Ochs RL, Muro Y, Si Y, Ge H, Chan EK, Tan EM | title = Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions | journal = J. Allergy Clin. Immunol. | volume = 105 | issue = 6 Pt 1 | pages = 1211–20 | year = 2000 | pmid = 10856157 | doi = 10.1067/mai.2000.107039 | doi-access = free }}
• {{cite journal | vauthors = Kubo E, Fatma N, Sharma P, Shinohara T, Chylack LT, Akagi Y, Singh DP | title = Transactivation of involucrin, a marker of differentiation in keratinocytes, by lens epithelium-derived growth factor (LEDGF) | journal = J. Mol. Biol. | volume = 320 | issue = 5 | pages = 1053–63 | year = 2002 | pmid = 12126624 | doi = 10.1016/S0022-2836(02)00551-X }}
• {{cite journal | vauthors = Wu X, Daniels T, Molinaro C, Lilly MB, Casiano CA | title = Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders | journal = Cell Death Differ. | volume = 9 | issue = 9 | pages = 915–25 | year = 2002 | pmid = 12181742 | doi = 10.1038/sj.cdd.4401063 | doi-access = free }}
• {{cite journal | vauthors = Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z | title = HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells | journal = J. Biol. Chem. | volume = 278 | issue = 1 | pages = 372–81 | year = 2003 | pmid = 12407101 | doi = 10.1074/jbc.M209278200 | doi-access = free }}
• {{cite journal | vauthors = Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, Engelborghs Y | title = LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells | journal = J. Biol. Chem. | volume = 278 | issue = 35 | pages = 33528–39 | year = 2003 | pmid = 12796494 | doi = 10.1074/jbc.M303594200 | doi-access = free }}
• {{cite journal | vauthors = Maertens G, Cherepanov P, Debyser Z, Engelborghs Y, Engelman A | title = Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75 | journal = J. Biol. Chem. | volume = 279 | issue = 32 | pages = 33421–9 | year = 2004 | pmid = 15163664 | doi = 10.1074/jbc.M404700200 | doi-access = free }}
• {{cite journal | vauthors = Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP | title = Large-scale characterization of HeLa cell nuclear phosphoproteins | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 33 | pages = 12130–5 | year = 2004 | pmid = 15302935 | pmc = 514446 | doi = 10.1073/pnas.0404720101 | bibcode = 2004PNAS..10112130B | doi-access = free }}
• {{cite journal | vauthors = Llano M, Vanegas M, Fregoso O, Saenz D, Chung S, Peretz M, Poeschla EM | title = LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes | journal = J. Virol. | volume = 78 | issue = 17 | pages = 9524–37 | year = 2004 | pmid = 15308744 | pmc = 506940 | doi = 10.1128/JVI.78.17.9524-9537.2004 }}
• {{cite journal | vauthors = Cherepanov P, Devroe E, Silver PA, Engelman A | title = Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase | journal = J. Biol. Chem. | volume = 279 | issue = 47 | pages = 48883–92 | year = 2004 | pmid = 15371438 | doi = 10.1074/jbc.M406307200 | doi-access = free }}
• {{cite journal | vauthors = Llano M, Delgado S, Vanegas M, Poeschla EM | title = Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase | journal = J. Biol. Chem. | volume = 279 | issue = 53 | pages = 55570–7 | year = 2004 | pmid = 15475359 | doi = 10.1074/jbc.M408508200 | doi-access = free }}
• {{cite journal | vauthors = Ogawa Y, Sugiura K, Watanabe A, Kunimatsu M, Mishima M, Tomita Y, Muro Y | title = Autoantigenicity of DFS70 is restricted to the conformational epitope of C-terminal alpha-helical domain | journal = J. Autoimmun. | volume = 23 | issue = 3 | pages = 221–31 | year = 2004 | pmid = 15501393 | doi = 10.1016/j.jaut.2004.07.003 }}
• {{cite journal | vauthors = Okamoto M, Ogawa Y, Watanabe A, Sugiura K, Shimomura Y, Aoki N, Nagasaka T, Tomita Y, Muro Y | title = Autoantibodies to DFS70/LEDGF are increased in alopecia areata patients | journal = J. Autoimmun. | volume = 23 | issue = 3 | pages = 257–66 | year = 2004 | pmid = 15501396 | doi = 10.1016/j.jaut.2004.07.004 }}

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