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 PSIP1gene.[5][6]
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[7] and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels.[8][9][10] The interaction between HIV
integrase and human LEDGF/p75 is a promising target for anti-HIV drug discovery.[11] LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression.[12] LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing,[13] also regulates HOTTIP lncRNA, which is shown to regulate HOX genes in cis.[14]
Structure
LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.[15] 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,[16] 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.
^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.
PMID10721720.
^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.
PMID20473303.
S2CID37421436.
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.
PMID15875659.
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.
PMID16403635.
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.
PMID10623627.
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.
PMID10721720.
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.
PMID12126624.
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.
PMID15501393.
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.
PMID15501396.
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 PSIP1gene.[5][6]
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[7] and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels.[8][9][10] The interaction between HIV
integrase and human LEDGF/p75 is a promising target for anti-HIV drug discovery.[11] LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression.[12] LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing,[13] also regulates HOTTIP lncRNA, which is shown to regulate HOX genes in cis.[14]
Structure
LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.[15] 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,[16] 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.
^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.
PMID10721720.
^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.
PMID20473303.
S2CID37421436.
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.
PMID15875659.
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.
PMID16403635.
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.
PMID10623627.
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.
PMID10721720.
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.
PMID12126624.
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.
PMID15501393.
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.
PMID15501396.
