PQBP1

{{Short description|Protein-coding gene in the species Homo sapiens}}

Polyglutamine-binding protein 1 (PQBP1) is a protein that in humans is encoded by the PQBP1 gene.{{cite journal | vauthors = Imafuku I, Waragai M, Takeuchi S, Kanazawa I, Kawabata M, Mouradian MM, Okazawa H | title = Polar amino acid-rich sequences bind to polyglutamine tracts | journal = Biochemical and Biophysical Research Communications | volume = 253 | issue = 1 | pages = 16–20 | date = December 1998 | pmid = 9875212 | doi = 10.1006/bbrc.1998.9725 }}{{cite journal | vauthors = Lenski C, Abidi F, Meindl A, Gibson A, Platzer M, Frank Kooy R, Lubs HA, Stevenson RE, Ramser J, Schwartz CE | display-authors = 6 | title = Novel truncating mutations in the polyglutamine tract binding protein 1 gene (PQBP1) cause Renpenning syndrome and X-linked mental retardation in another family with microcephaly | journal = American Journal of Human Genetics | volume = 74 | issue = 4 | pages = 777–780 | date = April 2004 | pmid = 15024694 | pmc = 1181956 | doi = 10.1086/383205 }}{{cite journal | vauthors = Waragai M, Lammers CH, Takeuchi S, Imafuku I, Udagawa Y, Kanazawa I, Kawabata M, Mouradian MM, Okazawa H | display-authors = 6 | title = PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival | journal = Human Molecular Genetics | volume = 8 | issue = 6 | pages = 977–987 | date = June 1999 | pmid = 10332029 | doi = 10.1093/hmg/8.6.977 | doi-access = free }}

Polyglutamine binding protein-1, which was identified as a binding protein to the polyglutamine tract sequence, is an evolutionally conserved protein{{cite journal | vauthors = Okazawa H, Sudol M, Rich T | title = PQBP-1 (Np/PQ): a polyglutamine tract-binding and nuclear inclusion-forming protein | journal = Brain Research Bulletin | volume = 56 | issue = 3–4 | pages = 273–280 | date = November 2001 | pmid = 11719261 | doi = 10.1016/S0361-9230(01)00579-2 | s2cid = 25290878 }} expressed in various tissues including developmental{{cite journal | vauthors = Qi Y, Hoshino M, Wada Y, Marubuchi S, Yoshimura N, Kanazawa I, Shinomiya K, Okazawa H | display-authors = 6 | title = PQBP-1 is expressed predominantly in the central nervous system during development | journal = The European Journal of Neuroscience | volume = 22 | issue = 6 | pages = 1277–1286 | date = September 2005 | pmid = 16190883 | doi = 10.1111/j.1460-9568.2005.04339.x | s2cid = 33492223 }} and adult brains or mesodermal tissues.{{cite journal | vauthors = Iwasaki Y, Thomsen GH | title = The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling | journal = Development | volume = 141 | issue = 19 | pages = 3740–3751 | date = October 2014 | pmid = 25209246 | pmc = 4197583 | doi = 10.1242/dev.106658 }} In cells, PQBP1 is dominantly located in the nucleus but also in the cytoplasm dependently on the cell type and stress conditions.{{cite journal | vauthors = Kunde SA, Musante L, Grimme A, Fischer U, Müller E, Wanker EE, Kalscheuer VM | title = The X-chromosome-linked intellectual disability protein PQBP1 is a component of neuronal RNA granules and regulates the appearance of stress granules | journal = Human Molecular Genetics | volume = 20 | issue = 24 | pages = 4916–4931 | date = December 2011 | pmid = 21933836 | doi = 10.1093/hmg/ddr430 | doi-access = free }} PQBP1 has recently been found to play a role in the innate immune response of dendritic cells.{{cite journal | vauthors = Yoh SM, Schneider M, Seifried J, Soonthornvacharin S, Akleh RE, Olivieri KC, De Jesus PD, Ruan C, de Castro E, Ruiz PA, Germanaud D, des Portes V, García-Sastre A, König R, Chanda SK | display-authors = 6 | title = PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1 | journal = Cell | volume = 161 | issue = 6 | pages = 1293–1305 | date = June 2015 | pmid = 26046437 | pmc = 4503237 | doi = 10.1016/j.cell.2015.04.050 | doi-access = free }}

It should be of note that PQBP1 has no relationship with QBP1, an artificial synthetic peptide.

Function

PQBP1 is a nuclear polyglutamine-binding protein that contains a WW domain.{{cite web | title = OMIM: PQBP1 polyglutamine binding protein 1| url =https://www.omim.org/entry/300463}}

The molecular roles of PQBP1 are mainly in mRNA splicing{{cite journal | vauthors = Okazawa H | title = PQBP1, an intrinsically disordered/denatured protein at the crossroad of intellectual disability and neurodegenerative diseases | journal = Neurochemistry International | volume = 119 | pages = 17–25 | date = October 2018 | pmid = 28627366 | doi = 10.1016/j.neuint.2017.06.005 | s2cid = 28886506 | doi-access = free }} and transcription.{{cite journal | vauthors = Okazawa H, Rich T, Chang A, Lin X, Waragai M, Kajikawa M, Enokido Y, Komuro A, Kato S, Shibata M, Hatanaka H, Mouradian MM, Sudol M, Kanazawa I | display-authors = 6 | title = Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death | journal = Neuron | volume = 34 | issue = 5 | pages = 701–713 | date = May 2002 | pmid = 12062018 | doi = 10.1016/S0896-6273(02)00697-9 | s2cid = 17652186 | doi-access = free }}{{cite journal | vauthors = Mizuguchi M, Obita T, Serita T, Kojima R, Nabeshima Y, Okazawa H | title = Mutations in the PQBP1 gene prevent its interaction with the spliceosomal protein U5-15 kD | journal = Nature Communications | volume = 5 | pages = 3822 | date = April 2014 | pmid = 24781215 | doi = 10.1038/ncomms4822 | bibcode = 2014NatCo...5.3822M | doi-access = free }} PQBP1 interacts with splicing proteins{{cite journal | vauthors = Zhang Y, Lindblom T, Chang A, Sudol M, Sluder AE, Golemis EA | title = Evidence that dim1 associates with proteins involved in pre-mRNA splicing, and delineation of residues essential for dim1 interactions with hnRNP F and Npw38/PQBP-1 | journal = Gene | volume = 257 | issue = 1 | pages = 33–43 | date = October 2000 | pmid = 11054566 | doi = 10.1016/S0378-1119(00)00372-3 }}{{cite journal | vauthors = Waragai M, Junn E, Kajikawa M, Takeuchi S, Kanazawa I, Shibata M, Mouradian MM, Okazawa H | display-authors = 6 | title = PQBP-1/Npw38, a nuclear protein binding to the polyglutamine tract, interacts with U5-15kD/dim1p via the carboxyl-terminal domain | journal = Biochemical and Biophysical Research Communications | volume = 273 | issue = 2 | pages = 592–595 | date = July 2000 | pmid = 10873650 | doi = 10.1006/bbrc.2000.2992 }}{{cite journal | vauthors = Mizuguchi M, Obita T, Serita T, Kojima R, Nabeshima Y, Okazawa H | title = Mutations in the PQBP1 gene prevent its interaction with the spliceosomal protein U5-15 kD | journal = Nature Communications | volume = 5 | issue = 1 | pages = 3822 | date = April 2014 | pmid = 24781215 | doi = 10.1038/ncomms4822 | bibcode = 2014NatCo...5.3822M | doi-access = free }}{{cite journal | vauthors = Wang Q, Moore MJ, Adelmant G, Marto JA, Silver PA | title = PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth | journal = Genes & Development | volume = 27 | issue = 6 | pages = 615–626 | date = March 2013 | pmid = 23512658 | pmc = 3613609 | doi = 10.1101/gad.212308.112 }} and RNA-binding proteins.{{cite journal | vauthors = Komuro A, Saeki M, Kato S | title = Association of two nuclear proteins, Npw38 and NpwBP, via the interaction between the WW domain and a novel proline-rich motif containing glycine and arginine | journal = The Journal of Biological Chemistry | volume = 274 | issue = 51 | pages = 36513–36519 | date = December 1999 | pmid = 10593949 | doi = 10.1074/jbc.274.51.36513 | doi-access = free }}{{cite journal | vauthors = Llorian M, Beullens M, Andrés I, Ortiz JM, Bollen M | title = SIPP1, a novel pre-mRNA splicing factor and interactor of protein phosphatase-1 | journal = The Biochemical Journal | volume = 378 | issue = Pt 1 | pages = 229–238 | date = February 2004 | pmid = 14640981 | doi = 10.1042/bj20030950 | pmc = 1223944 }} PQBP1 deficiency critically affects mRNA splicing of cell cycle and synapse related genes. Recent results indicated implication of PQBP1 in cytoplasmic RNA metabolism{{cite journal | vauthors = Musante L, Kunde SA, Sulistio TO, Fischer U, Grimme A, Frints SG, Schwartz CE, Martínez F, Romano C, Ropers HH, Kalscheuer VM | display-authors = 6 | title = Common pathological mutations in PQBP1 induce nonsense-mediated mRNA decay and enhance exclusion of the mutant exon | journal = Human Mutation | volume = 31 | issue = 1 | pages = 90–98 | date = January 2010 | pmid = 19847789 | doi = 10.1002/humu.21146 | s2cid = 23152883 | doi-access = free }} and elongation of protein translation from mRNA.{{cite journal | vauthors = Shen Y, Zhang ZC, Cheng S, Liu A, Zuo J, Xia S, Liu X, Liu W, Jia Z, Xie W, Han J | display-authors = 6 | title = PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation | journal = Molecular Cell | volume = 81 | issue = 7 | pages = 1425–1438.e10 | date = April 2021 | pmid = 33662272 | doi = 10.1016/j.molcel.2021.01.032 | s2cid = 232122674 | doi-access = free }} Research also seems to suggest that PQBP1 also plays a role in the innate immune system as a necessary adaptor for the cGAS-mediated innate response to lentiviruses such as HIV1. This PQBP-1 dependent response initiates a sensor that detects lentiviral DNA.{{cite journal | vauthors = Yoh SM, Mamede JI, Lau D, Ahn N, Sánchez-Aparicio MT, Temple J, Tuckwell A, Fuchs NV, Cianci GC, Riva L, Curry H, Yin X, Gambut S, Simons LM, Hultquist JF, König R, Xiong Y, García-Sastre A, Böcking T, Hope TJ, Chanda SK | display-authors = 6 | title = Recognition of HIV-1 capsid by PQBP1 licenses an innate immune sensing of nascent HIV-1 DNA | journal = Molecular Cell | volume = 82 | issue = 15 | pages = 2871–2884.e6 | date = August 2022 | pmid = 35809572 | pmc = 9552964 | doi = 10.1016/j.molcel.2022.06.010 }}

Clinical significance

Mutations in the PQBP1 gene, which encodes for this protein, have been known to cause X-linked intellectual disabilities (XLID), commonly referred to as Renpenning's syndrome.{{cite journal | vauthors = Stevenson RE, Bennett CW, Abidi F, Kleefstra T, Porteous M, Simensen RJ, Lubs HA, Hamel BC, Schwartz CE | display-authors = 6 | title = Renpenning syndrome comes into focus | journal = American Journal of Medical Genetics. Part A | volume = 134 | issue = 4 | pages = 415–421 | date = May 2005 | pmid = 15782410 | doi = 10.1002/ajmg.a.30664 | s2cid = 24333408 }} Recent studies indicate that PQBP-1 interaction with TXNL4A is missing in patients with frameshift mutations causing Renpenning's syndrome. PQBP-1 seems to facilitate the nuclear import of TXNL4A, however the biological function of that interaction requires further investigation.{{cite journal | vauthors = Liu X, Dou LX, Han J, Zhang ZC | title = The Renpenning syndrome-associated protein PQBP1 facilitates the nuclear import of splicing factor TXNL4A through the karyopherin β2 receptor | journal = The Journal of Biological Chemistry | volume = 295 | issue = 13 | pages = 4093–4100 | date = March 2020 | pmid = 32041777 | pmc = 7105315 | doi = 10.1074/jbc.RA119.012214 | doi-access = free }} People who suffer from these disabilities share a common set of symptoms including: microcephaly, shortened stature and impaired intellectual development.{{cite journal | vauthors = Kalscheuer VM, Freude K, Musante L, Jensen LR, Yntema HG, Gécz J, Sefiani A, Hoffmann K, Moser B, Haas S, Gurok U, Haesler S, Aranda B, Nshedjan A, Tzschach A, Hartmann N, Roloff TC, Shoichet S, Hagens O, Tao J, Van Bokhoven H, Turner G, Chelly J, Moraine C, Fryns JP, Nuber U, Hoeltzenbein M, Scharff C, Scherthan H, Lenzner S, Hamel BC, Schweiger S, Ropers HH | display-authors = 6 | title = Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation | journal = Nature Genetics | volume = 35 | issue = 4 | pages = 313–315 | date = December 2003 | pmid = 14634649 | doi = 10.1038/ng1264 | hdl = 11858/00-001M-0000-0010-8953-D | s2cid = 27007340 | hdl-access = free }} There are 11 types of mutations that have been identified, but the most common being frameshift mutations.{{cite journal | vauthors = Germanaud D, Rossi M, Bussy G, Gérard D, Hertz-Pannier L, Blanchet P, Dollfus H, Giuliano F, Bennouna-Greene V, Sarda P, Sigaudy S, Curie A, Vincent MC, Touraine R, des Portes V | display-authors = 6 | title = The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males | journal = Clinical Genetics | volume = 79 | issue = 3 | pages = 225–235 | date = March 2011 | pmid = 20950397 | doi = 10.1111/j.1399-0004.2010.01551.x | s2cid = 22909872 }} Other syndromic XLIDs such as Golabi-Ito-Hall syndrome and non-syndromic ID patients were also associated with PQBP1 gene mutations.{{cite journal | vauthors = Lubs H, Abidi FE, Echeverri R, Holloway L, Meindl A, Stevenson RE, Schwartz CE | title = Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene | journal = Journal of Medical Genetics | volume = 43 | issue = 6 | pages = e30 | date = June 2006 | pmid = 16740914 | doi = 10.1136/jmg.2005.037556 | pmc = 2564547 }}{{cite journal | vauthors = Tapia VE, Nicolaescu E, McDonald CB, Musi V, Oka T, Inayoshi Y, Satteson AC, Mazack V, Humbert J, Gaffney CJ, Beullens M, Schwartz CE, Landgraf C, Volkmer R, Pastore A, Farooq A, Bollen M, Sudol M | display-authors = 6 | title = Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing | journal = The Journal of Biological Chemistry | volume = 285 | issue = 25 | pages = 19391–19401 | date = June 2010 | pmid = 20410308 | doi = 10.1074/jbc.M109.084525 | pmc = 2885219 | doi-access = free }}{{cite journal | vauthors = Sudol M, McDonald CB, Farooq A | title = Molecular insights into the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 | journal = FEBS Letters | volume = 586 | issue = 17 | pages = 2795–2799 | date = August 2012 | pmid = 22710169 | doi = 10.1016/j.febslet.2012.03.041 | pmc = 3413755 }}

Mutant Ataxin-1 and Huntingtin, disease proteins of spinocerebellar ataxia type-1 and Huntington's disease respectively, interact with PQBP1 and disturbed the functions of PQBP1.{{cite journal | vauthors = Busch A, Engemann S, Lurz R, Okazawa H, Lehrach H, Wanker EE | title = Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: a potential mechanism for loss of huntingtin function in Huntington's disease | journal = The Journal of Biological Chemistry | volume = 278 | issue = 42 | pages = 41452–41461 | date = October 2003 | pmid = 12888569 | doi = 10.1074/jbc.M303354200 | doi-access = free }} Moreover, recent investigations revealed pathological roles of PQBP1 in neurons{{cite journal | vauthors = Tanaka H, Kondo K, Chen X, Homma H, Tagawa K, Kerever A, Aoki S, Saito T, Saido T, Muramatsu SI, Fujita K, Okazawa H | display-authors = 6 | title = The intellectual disability gene PQBP1 rescues Alzheimer's disease pathology | journal = Molecular Psychiatry | volume = 23 | issue = 10 | pages = 2090–2110 | date = October 2018 | pmid = 30283027 | doi = 10.1038/s41380-018-0253-8 | pmc = 6250680 }} and microglia{{cite journal | vauthors = Jin M, Shiwaku H, Tanaka H, Obita T, Ohuchi S, Yoshioka Y, Jin X, Kondo K, Fujita K, Homma H, Nakajima K, Mizuguchi M, Okazawa H | display-authors = 6 | title = Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation | journal = Nature Communications | volume = 12 | issue = 1 | pages = 6565 | date = November 2021 | pmid = 34782623 | doi = 10.1038/s41467-021-26851-2 | pmc = 8592984 | bibcode = 2021NatCo..12.6565J }} under neurodegeneration of Alzheimer's disease and tauopathy. SRRM2 phosphorylation detected in neurons at the early stage of Alzheimer's disease pathology{{cite journal | vauthors = Tagawa K, Homma H, Saito A, Fujita K, Chen X, Imoto S, Oka T, Ito H, Motoki K, Yoshida C, Hatsuta H, Murayama S, Iwatsubo T, Miyano S, Okazawa H | display-authors = 6 | title = Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer's disease brain | journal = Human Molecular Genetics | volume = 24 | issue = 2 | pages = 540–558 | date = January 2015 | pmid = 25231903 | doi = 10.1093/hmg/ddu475 | doi-access = free }} leads to reduction of SRRM2, a scaffold protein for RNA metabolism related molecules in the nucleus, which causes reduction of PQBP1 in the nucleus and acquired intellectual disability. PQBP1 was shown as an intracellular receptor for HIV1 in dendritic cells{{cite journal | vauthors = Yoh SM, Schneider M, Seifried J, Soonthornvacharin S, Akleh RE, Olivieri KC, De Jesus PD, Ruan C, de Castro E, Ruiz PA, Germanaud D, des Portes V, García-Sastre A, König R, Chanda SK | display-authors = 6 | title = PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1 | journal = Cell | volume = 161 | issue = 6 | pages = 1293–1305 | date = June 2015 | pmid = 26046437 | doi = 10.1016/j.cell.2015.04.050 | pmc = 4503237 }} for innate immune system. Recent studies indicate that PQBP1 recognizes intact capsids of HIV-1 particles. It interacts with these capsids through its amino-terminus, and when capsid disassembles it triggers the PQBP-1 dependent recruitment of cGAS. This is crucial to activating the sensor that detects HIV-1 DNA as soon as synthesis is initiated. Similarly, PQBP1 functions as an intracellular receptor for tau proteins and trigger brain inflammation.

Animal models

Mouse models of knockdown and conditional knockout were generated, and they showed cognitive impairment and microcephaly.{{cite journal | vauthors = Ito H, Yoshimura N, Kurosawa M, Ishii S, Nukina N, Okazawa H | title = Knock-down of PQBP1 impairs anxiety-related cognition in mouse | journal = Human Molecular Genetics | volume = 18 | issue = 22 | pages = 4239–4254 | date = November 2009 | pmid = 19661183 | doi = 10.1093/hmg/ddp378 | doi-access = free }}{{cite journal | vauthors = Ito H, Shiwaku H, Yoshida C, Homma H, Luo H, Chen X, Fujita K, Musante L, Fischer U, Frints SG, Romano C, Ikeuchi Y, Shimamura T, Imoto S, Miyano S, Muramatsu SI, Kawauchi T, Hoshino M, Sudol M, Arumughan A, Wanker EE, Rich T, Schwartz C, Matsuzaki F, Bonni A, Kalscheuer VM, Okazawa H | display-authors = 6 | title = In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells | journal = Molecular Psychiatry | volume = 20 | issue = 4 | pages = 459–471 | date = April 2015 | pmid = 25070536 | doi = 10.1038/mp.2014.69 | pmc = 4378255 }} The KD mice possess a transgene expressing 498 bp double-strand RNA that is endogenously cleaved to siRNA suppressing PQBP1 efficiently, and did not show obvious developmental abnormality. Another knockdown model of the gene in mouse embryo primary neurons revealed a decrease in splicing efficiency and resulted in abnormal gastrulation and neuralation patterning.

Drosophila models of underexpression and overexpression were also generated.{{cite journal | vauthors = Tamura T, Horiuchi D, Chen YC, Sone M, Miyashita T, Saitoe M, Yoshimura N, Chiang AS, Okazawa H | display-authors = 6 | title = Drosophila PQBP1 regulates learning acquisition at projection neurons in aversive olfactory conditioning | journal = The Journal of Neuroscience | volume = 30 | issue = 42 | pages = 14091–14101 | date = October 2010 | pmid = 20962230 | doi = 10.1523/JNEUROSCI.1319-10.2010 | pmc = 6634781 }}{{cite journal | vauthors = Yoshimura N, Horiuchi D, Shibata M, Saitoe M, Qi ML, Okazawa H | title = Expression of human PQBP-1 in Drosophila impairs long-term memory and induces abnormal courtship | journal = FEBS Letters | volume = 580 | issue = 9 | pages = 2335–2340 | date = April 2006 | pmid = 16597440 | doi = 10.1016/j.febslet.2006.03.056 | s2cid = 21490164 | doi-access = free }} The hypomorph Drosophila model revealed molecular function of PQBP1 in learning acquisition mediated by decreased mRNA and protein expressions of NMDA receptor subunit NR1. Research indicates that in order to appropriately function, the protein must be expressed within a critical range.{{cite journal | vauthors = Tamura T, Sone M, Nakamura Y, Shimamura T, Imoto S, Miyano S, Okazawa H | title = A restricted level of PQBP1 is needed for the best longevity of Drosophila | journal = Neurobiology of Aging | volume = 34 | issue = 1 | pages = 356.e11–356.e20 | date = January 2013 | pmid = 22901698 | doi = 10.1016/j.neurobiolaging.2012.07.015 | s2cid = 17527056 }}

References

External links

{{UCSC genome browser|PQBP1}}
{{UCSC gene details|PQBP1}}
{{PDBe-KB2|O60828|Polyglutamine-binding protein 1}}