Polyglutamine-binding protein 1 (PQBP1) is a protein that in humans is encoded by the PQBP1 gene.[5][6][7]
Polyglutamine binding protein-1, which was identified as a binding protein to the polyglutamine tract sequence,[5][7] is an evolutionally conserved protein[8] expressed in various tissues including developmental[9] and adult brains[7] or mesodermal tissues.[10] In cells, PQBP1 is dominantly located in the nucleus[7][11] but also in the cytoplasm dependently on the cell type[12] and stress conditions.[13]PQBP1 has recently been found to play a role in the innate immune response of dendritic cells.[14]
It should be of note that PQBP1 has no relationship with QBP1, an artificial synthetic peptide.
PQBP1 is a nuclear polyglutamine-binding protein that contains a WW domain.[7][15]
The molecular roles of PQBP1 are mainly in mRNA splicing[16][17] and transcription.[11][18] PQBP1 interacts with splicing proteins[19][20][21][22] and RNA-binding proteins.[23][24] PQBP1 deficiency critically affects mRNA splicing of cell cycle and synapse related genes.[16] Recent results indicated implication of PQBP1 in cytoplasmic RNA metabolism[25] and elongation of protein translation from mRNA.[26]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.[27]
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.[28]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.[29] People who suffer from these disabilities share a common set of symptoms including: microcephaly, shortened stature and impaired intellectual development.[30] There are 11 types of mutations that have been identified, but the most common being frameshift mutations.[28][31] Other syndromic XLIDs such as Golabi-Ito-Hall syndrome and non-syndromic ID patients were also associated with PQBP1 gene mutations.[32][33][34]
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.[11][35] Moreover, recent investigations revealed pathological roles of PQBP1 in neurons[36] and microglia[12] under neurodegeneration of Alzheimer's disease and tauopathy. SRRM2 phosphorylation detected in neurons at the early stage of Alzheimer's disease pathology[37] 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.[36] PQBP1 was shown as an intracellular receptor for HIV1 in dendritic cells[38] 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.[39] Similarly, PQBP1 functions as an intracellular receptor for tau proteins and trigger brain inflammation.[12]
Mouse models of knockdown and conditional knockout were generated, and they showed cognitive impairment and microcephaly.[40][16] 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.[40] 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.[10]
Drosophila models of underexpression and overexpression were also generated.[41][42] The hypomorph Drosophila model revealed molecular function of PQBP1 in learning acquisition mediated by decreased mRNA and protein expressions of NMDA receptor subunit NR1.[41] Research indicates that in order to appropriately function, the protein must be expressed within a critical range.[43][10]