PSIP1

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Identifiers
Aliases
External IDs	GeneCards: [1]
Orthologs
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a
Wikidata
View/Edit Human

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.

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

Structure

LEDGF/p75 is a 60kDa, 530-amino-acid-long protein. 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, 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.

Further reading

• Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A (July 2007). "LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration". Genes Dev. 21 (14): 1767–78. doi:10.1101/gad.1565107. PMC 1920171. PMID 17639082.
• Van Maele B, Debyser Z (2005). "HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins". AIDS Rev. 7 (1): 26–43. PMID 15875659.
• Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z (2006). "Cellular co-factors of HIV-1 integration". Trends Biochem. Sci. 31 (2): 98–105. doi:10.1016/j.tibs.2005.12.002. PMID 16403635.
• Freed EO, Mouland AJ (2006). "The cell biology of HIV-1 and other retroviruses". Retrovirology. 3: 77. doi:10.1186/1742-4690-3-77. PMC 1635732. PMID 17083721.
• Ge H, Si Y, Roeder RG (1998). "Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation". EMBO J. 17 (22): 6723–9. doi:10.1093/emboj/17.22.6723. PMC 1171017. PMID 9822615.
• Ge H, Si Y, Wolffe AP (1998). "A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2". Mol. Cell. 2 (6): 751–9. doi:10.1016/S1097-2765(00)80290-7. PMID 9885563.
• Singh DP, Ohguro N, Kikuchi T, Sueno T, Reddy VN, Yuge K, Chylack LT, Shinohara T (2000). "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. doi:10.1006/bbrc.1999.1979. PMID 10623627.
• Singh DP, Kimura A, Chylack LT, Shinohara T (2000). "Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing". Gene. 242 (1–2): 265–73. doi:10.1016/S0378-1119(99)00506-5. PMID 10721720.
• Ochs RL, Muro Y, Si Y, Ge H, Chan EK, Tan EM (2000). "Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions". J. Allergy Clin. Immunol. 105 (6 Pt 1): 1211–20. doi:10.1067/mai.2000.107039. PMID 10856157.
• Kubo E, Fatma N, Sharma P, Shinohara T, Chylack LT, Akagi Y, Singh DP (2002). "Transactivation of involucrin, a marker of differentiation in keratinocytes, by lens epithelium-derived growth factor (LEDGF)". J. Mol. Biol. 320 (5): 1053–63. doi:10.1016/S0022-2836(02)00551-X. PMID 12126624.
• Wu X, Daniels T, Molinaro C, Lilly MB, Casiano CA (2002). "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. doi:10.1038/sj.cdd.4401063. PMID 12181742.
• Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z (2003). "HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells". J. Biol. Chem. 278 (1): 372–81. doi:10.1074/jbc.M209278200. PMID 12407101.
• Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, Engelborghs Y (2003). "LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells". J. Biol. Chem. 278 (35): 33528–39. doi:10.1074/jbc.M303594200. PMID 12796494.
• Maertens G, Cherepanov P, Debyser Z, Engelborghs Y, Engelman A (2004). "Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75". J. Biol. Chem. 279 (32): 33421–9. doi:10.1074/jbc.M404700200. PMID 15163664.
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–5. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
• Llano M, Vanegas M, Fregoso O, Saenz D, Chung S, Peretz M, Poeschla EM (2004). "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. doi:10.1128/JVI.78.17.9524-9537.2004. PMC 506940. PMID 15308744.
• Cherepanov P, Devroe E, Silver PA, Engelman A (2004). "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. doi:10.1074/jbc.M406307200. PMID 15371438.
• Llano M, Delgado S, Vanegas M, Poeschla EM (2004). "Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase". J. Biol. Chem. 279 (53): 55570–7. doi:10.1074/jbc.M408508200. PMID 15475359.
• Ogawa Y, Sugiura K, Watanabe A, Kunimatsu M, Mishima M, Tomita Y, Muro Y (2004). "Autoantigenicity of DFS70 is restricted to the conformational epitope of C-terminal alpha-helical domain". J. Autoimmun. 23 (3): 221–31. doi:10.1016/j.jaut.2004.07.003. PMID 15501393.
• Okamoto M, Ogawa Y, Watanabe A, Sugiura K, Shimomura Y, Aoki N, Nagasaka T, Tomita Y, Muro Y (2004). "Autoantibodies to DFS70/LEDGF are increased in alopecia areata patients". J. Autoimmun. 23 (3): 257–66. doi:10.1016/j.jaut.2004.07.004. PMID 15501396.