PSIP1 explained

PC4 and SFRS1 interacting protein 1, also known as lens epithelium-derived growth factor (LEDGF/p75), dense fine speckles 70kD protein (DFS 70) or transcriptional coactivator p75/p52, is a protein that in humans is encoded by the PSIP1 gene.^{[1] [2]}

Function

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^[3] and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels.^{[4] [5] [6]} The interaction between HIV integrase and human LEDGF/p75 is a promising target for anti-HIV drug discovery.^[7] LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression.^[8] LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing,^[9] also regulates HOTTIP lncRNA, which is shown to regulate HOX genes in cis.^[10]

Structure

LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.^[11] 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,^[12] 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.

Interactions

PSIP1 has been shown to interact with the proteins ASF/SF2, JPO2, Cdc7-Dbf4, and POGZ as well as the menin/MLL protein complex.^{[13] [14]}

Further reading

• Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A . LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration . Genes Dev. . 21 . 14 . 1767–78 . July 2007 . 17639082 . 1920171 . 10.1101/gad.1565107 .
• Van Maele B, Debyser Z . HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins . AIDS Rev . 7 . 1 . 26–43 . 2005 . 15875659 .
• Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z . Cellular co-factors of HIV-1 integration . Trends Biochem. Sci. . 31 . 2 . 98–105 . 2006 . 16403635 . 10.1016/j.tibs.2005.12.002 .
• Freed EO, Mouland AJ . The cell biology of HIV-1 and other retroviruses . Retrovirology . 3 . 77 . 2006 . 17083721 . 1635732 . 10.1186/1742-4690-3-77 . free .
• Ge H, Si Y, Roeder RG . Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation . EMBO J. . 17 . 22 . 6723–9 . 1998 . 9822615 . 1171017 . 10.1093/emboj/17.22.6723 .
• Ge H, Si Y, Wolffe AP . A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2 . Mol. Cell . 2 . 6 . 751–9 . 1998 . 9885563 . 10.1016/S1097-2765(00)80290-7 . free .
• Singh DP, Ohguro N, Kikuchi T, Sueno T, Reddy VN, Yuge K, Chylack LT, Shinohara T . Lens epithelium-derived growth factor: effects on growth and survival of lens epithelial cells, keratinocytes, and fibroblasts . Biochem. Biophys. Res. Commun. . 267 . 1 . 373–81 . 2000 . 10623627 . 10.1006/bbrc.1999.1979 .
• Singh DP, Kimura A, Chylack LT, Shinohara T . Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing . Gene . 242 . 1–2 . 265–73 . 2000 . 10721720 . 10.1016/S0378-1119(99)00506-5 .
• Ochs RL, Muro Y, Si Y, Ge H, Chan EK, Tan EM . Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions . J. Allergy Clin. Immunol. . 105 . 6 Pt 1 . 1211–20 . 2000 . 10856157 . 10.1067/mai.2000.107039 . free .
• Kubo E, Fatma N, Sharma P, Shinohara T, Chylack LT, Akagi Y, Singh DP . Transactivation of involucrin, a marker of differentiation in keratinocytes, by lens epithelium-derived growth factor (LEDGF) . J. Mol. Biol. . 320 . 5 . 1053–63 . 2002 . 12126624 . 10.1016/S0022-2836(02)00551-X .
• Wu X, Daniels T, Molinaro C, Lilly MB, Casiano CA . Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders . Cell Death Differ. . 9 . 9 . 915–25 . 2002 . 12181742 . 10.1038/sj.cdd.4401063 . free .
• Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z . HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells . J. Biol. Chem. . 278 . 1 . 372–81 . 2003 . 12407101 . 10.1074/jbc.M209278200 . free .
• Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, Engelborghs Y . LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells . J. Biol. Chem. . 278 . 35 . 33528–39 . 2003 . 12796494 . 10.1074/jbc.M303594200 . free .
• Maertens G, Cherepanov P, Debyser Z, Engelborghs Y, Engelman A . Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75 . J. Biol. Chem. . 279 . 32 . 33421–9 . 2004 . 15163664 . 10.1074/jbc.M404700200 . free .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proc. Natl. Acad. Sci. U.S.A. . 101 . 33 . 12130–5 . 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Llano M, Vanegas M, Fregoso O, Saenz D, Chung S, Peretz M, Poeschla EM . LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes . J. Virol. . 78 . 17 . 9524–37 . 2004 . 15308744 . 506940 . 10.1128/JVI.78.17.9524-9537.2004 .
• Cherepanov P, Devroe E, Silver PA, Engelman A . Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase . J. Biol. Chem. . 279 . 47 . 48883–92 . 2004 . 15371438 . 10.1074/jbc.M406307200 . free .
• Llano M, Delgado S, Vanegas M, Poeschla EM . Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase . J. Biol. Chem. . 279 . 53 . 55570–7 . 2004 . 15475359 . 10.1074/jbc.M408508200 . free .
• Ogawa Y, Sugiura K, Watanabe A, Kunimatsu M, Mishima M, Tomita Y, Muro Y . Autoantigenicity of DFS70 is restricted to the conformational epitope of C-terminal alpha-helical domain . J. Autoimmun. . 23 . 3 . 221–31 . 2004 . 15501393 . 10.1016/j.jaut.2004.07.003 .
• Okamoto M, Ogawa Y, Watanabe A, Sugiura K, Shimomura Y, Aoki N, Nagasaka T, Tomita Y, Muro Y . Autoantibodies to DFS70/LEDGF are increased in alopecia areata patients . J. Autoimmun. . 23 . 3 . 257–66 . 2004 . 15501396 . 10.1016/j.jaut.2004.07.004 .

Notes and References

1. Web site: Entrez Gene: PSIP1 PC4 and SFRS1 interacting protein 1.
2. Singh DP, Kimura A, Chylack LT, Shinohara T . Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing . Gene . 242 . 1–2 . 265–73 . January 2000 . 10721720 . 10.1016/S0378-1119(99)00506-5 .
3. Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z . HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells . J. Biol. Chem. . 278 . 1 . 372–81 . January 2003 . 12407101 . 10.1074/jbc.M209278200 . free .
4. Vandekerckhove L, Christ F, Van Maele B, De Rijck J, Gijsbers R, Van den Haute C, Witvrouw M, Debyser Z . Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus . J. Virol. . 80 . 4 . 1886–96 . February 2006 . 16439544 . 1367129 . 10.1128/JVI.80.4.1886-1896.2006 .
5. Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A . LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration . Genes Dev. . 21 . 14 . 1767–78 . July 2007 . 17639082 . 1920171 . 10.1101/gad.1565107 .
6. Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, Teo W, Poeschla EM . An essential role for LEDGF/p75 in HIV integration . Science . 314 . 5798 . 461–4 . October 2006 . 16959972 . 10.1126/science.1132319 . 2006Sci...314..461L . 24756699 .
7. 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 . Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication . Nat. Chem. Biol. . 6 . 6 . 442–8 . June 2010 . 20473303 . 10.1038/nchembio.370 . 37421436 .
8. Pradeepa. Madapura M.. Grimes. Graeme R.. Taylor. Gillian C. A.. Sutherland. Heidi G.. Bickmore. Wendy A.. 2014-08-18. Psip1/Ledgf p75 restrains Hox gene expression by recruiting both trithorax and polycomb group proteins. Nucleic Acids Research. 42. 14. 9021–9032. 10.1093/nar/gku647. 0305-1048. 4132756. 25056311.
9. Pradeepa. Madapura M.. Sutherland. Heidi G.. Ule. Jernej. Grimes. Graeme R.. Bickmore. Wendy A.. 2012-05-17. Psip1/Ledgf p52 Binds Methylated Histone H3K36 and Splicing Factors and Contributes to the Regulation of Alternative Splicing. PLOS Genetics. 8. 5. e1002717. 10.1371/journal.pgen.1002717. 1553-7404. 3355077. 22615581 . free .
10. Pradeepa. Madapura M.. McKenna. Fionnuala. Taylor. Gillian C. A.. Bengani. Hemant. Grimes. Graeme R.. Wood. Andrew J.. Bhatia. Shipra. Bickmore. Wendy A.. 2017-04-06. Psip1/p52 regulates posterior Hoxa genes through activation of lncRNA Hottip. PLOS Genetics. 13. 4. e1006677. 10.1371/journal.pgen.1006677. 1553-7404. 5383017. 28384324 . free .
11. Book: Eric Poeschla . Llano M, Morrison J, Poeschla EM . Virological and Cellular Roles of the Transcriptional Coactivator LEDGF/P75 . HIV Interactions with Host Cell Proteins . Curr. Top. Microbiol. Immunol. . 339 . 125–46 . 2009 . 20012527 . 3093762 . 10.1007/978-3-642-02175-6_7 . Current Topics in Microbiology and Immunology . 978-3-642-02174-9 .
12. Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A . Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75 . Nat. Struct. Mol. Biol. . 12 . 6 . 526–32 . June 2005 . 15895093 . 10.1038/nsmb937. 20898124 .
13. Ge H, Si Y, Wolffe AP . A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2 . Mol. Cell . 2 . 6 . 751–9 . December 1998 . 9885563 . 10.1016/S1097-2765(00)80290-7 . free .
14. Hughes S, Jenkins V, Dar MJ, Engelman A, Cherepanov P . Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity . J. Biol. Chem. . 285 . 1 . 541–54 . January 2010 . 19864417 . 2804203 . 10.1074/jbc.M109.036491 . free .