PSIP1

PC4 and SFRS1 interacting protein 1
PDB rendering based on 1z9e.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1Z9E​, 2B4J​, 2M16​, 2MSR​, 2MTN​, 3F9K​, 3HPG​, 3HPH​, 3U88​, 3ZEH​, 4FU6​
Identifiers
Symbols	PSIP1 ; DFS70; LEDGF; PAIP; PSIP2; p52; p75
External IDs	OMIM: 603620 MGI: 2142116 HomoloGene: 13242 GeneCards: PSIP1 Gene
Gene ontology Molecular function • RNA polymerase II transcription coactivator activity • chromatin binding • protein binding • activating transcription factor binding • poly(A) RNA binding • supercoiled DNA binding Cellular component • nucleus • nucleoplasm • nuclear heterochromatin • nucleolus • cytosol • nuclear periphery • transcriptionally active chromatin Biological process • mRNA 5'-splice site recognition • transcription, DNA-templated • regulation of transcription, DNA-templated • response to oxidative stress • response to heat • viral process • positive regulation of transcription from RNA polymerase II promoter • establishment of integrated proviral latency Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	11168	101739
Ensembl	ENSG00000164985	ENSMUSG00000028484
UniProt	O75475	Q99JF8
RefSeq (mRNA)	NM_001128217	NM_001290527
RefSeq (protein)	NP_001121689	NP_001277456
Location (UCSC)	Chr 9: 15.46 – 15.51 Mb	Chr 4: 83.46 – 83.49 Mb
PubMed search

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]

Structure

LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.^[8] 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,^[9] 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.^[10][11]

References

1. "Entrez Gene: PSIP1 PC4 and SFRS1 interacting protein 1".
2. Singh DP, Kimura A, Chylack LT, Shinohara T (January 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.
3. Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z (January 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.
4. Vandekerckhove L, Christ F, Van Maele B, De Rijck J, Gijsbers R, Van den Haute C, Witvrouw M, Debyser Z (February 2006). "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. doi:10.1128/JVI.80.4.1886-1896.2006. PMC 1367129. PMID 16439544.
5. 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.
6. Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, Teo W, Poeschla EM (October 2006). "An essential role for LEDGF/p75 in HIV integration". Science 314 (5798): 461–4. doi:10.1126/science.1132319. PMID 16959972.
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 (June 2010). "Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication". Nat. Chem. Biol. 6 (6): 442–8. doi:10.1038/nchembio.370. PMID 20473303.
8. Llano M, Morrison J, Poeschla EM (2009). "Virological and cellular roles of the transcriptional coactivator LEDGF/p75". Curr. Top. Microbiol. Immunol. 339: 125–46. doi:10.1007/978-3-642-02175-6_7. PMC 3093762. PMID 20012527.
9. Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A (June 2005). "Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75". Nat. Struct. Mol. Biol. 12 (6): 526–32. doi:10.1038/nsmb93. PMID 15895093.
10. Ge H, Si Y, Wolffe AP (December 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.
11. Hughes S, Jenkins V, Dar MJ, Engelman A, Cherepanov P (January 2010). "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. doi:10.1074/jbc.M109.036491. PMC 2804203. PMID 19864417.

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.