Allosteric modulation of the binding affinity between <scp>PQBP</scp>1 and the spliceosomal protein U5‐15kD

Mizuguchi, Mineyuki; Obita, Takayuki; Kozakai, Yuki; Nakai, Takeshi; Nabeshima, Yuko; Okazawa, Hitoshi

doi:10.1002/1873-3468.12256

Cited by 9 publications

(8 citation statements)

References 40 publications

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“…Both PQBP1 and TXNL4A are evolutionarily conserved molecules and components of spliceosome (15,19,20,24,(31)(32)(33). The molecular interaction between them is wellestablished (14)(15)(16)(17)(18) but what is the biological function of this interaction remains unclear. TXNL4A is a member of the U5 spliceosomal complex and mainly functions in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…PQBP1 gene encodes an intrinsically disordered protein predominantly expressed in the central nervous system during development and playing important roles in neurodevelopment and neuronal functions (4)(5)(6)(7). PQBP1 is composed of three interacting domains: a WW domain interacting with the nucleocytoplasmic shuttling splicing factor WBP11 (8-10); a polar amino acid-rich domain (PRD) interacting with polyglutamine tracts (11,12), a PY nuclear localization signal (PY-NLS) recognized by nuclear import receptor karyopherin β2 (Kapβ2) (13) and an unstructured C-terminal domain (CTD) interacting with splicing factor TXNL4A (14)(15)(16)(17)(18). Despite its interaction with splicing factors, PQBP1 is also found present in the precatalytic B complex (19,20), suggesting the involvement of PQBP1 in alternative pre-mRNA splicing.…”

Section: Introductionmentioning

confidence: 99%

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The Renpenning syndrome–associated protein PQBP1 facilitates the nuclear import of splicing factor TXNL4A through the karyopherin β2 receptor

Liu

Dou

Han

et al. 2020

Journal of Biological Chemistry

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Renpenning syndrome belongs to a group of X-linked intellectual disability disorders. The Renpenning syndrome–associated protein PQBP1 (polyglutamine-binding protein 1) is intrinsically disordered, associates with several splicing factors, and is involved in pre-mRNA splicing. PQBP1 uses its C-terminal YxxPxxVL motif for binding to the splicing factor TXNL4A (thioredoxin like 4A), but the biological function of this interaction has yet to be elucidated. In this study, using recombinant protein expression, in vitro binding assays, and immunofluorescence microscopy in HeLa cells, we found that a recently reported X-linked intellectual disability–associated missense mutation, resulting in the PQBP1-P244L variant, disrupts the interaction with TXNL4A. We further show that this interaction is critical for the subcellular location of TXNL4A. In combination with other PQBP1 variants lacking a functional nuclear localization signal required for recognition by the nuclear import receptor karyopherin β2, we demonstrate that PQBP1 facilitates the nuclear import of TXNL4A via a piggyback mechanism. These findings expand our understanding of the molecular basis of the PQBP1–TXNL4A interaction and of the etiology and pathogenesis of Renpenning syndrome and related disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Renpenning syndrome–associated protein PQBP1 facilitates the nuclear import of splicing factor TXNL4A through the karyopherin β2 receptor

Liu

Dou

Han

et al. 2020

Journal of Biological Chemistry

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“…Interestingly, PQBP1 was originally identified as a binding protein to polyglutamine (polyQ) tract amino acid sequence that is expanded in a group of neurodegenerative diseases called polyQ diseases [11][12][13] . PQBP1 possesses a folded WW domain [14][15][16][17] and an unfolded C-terminal domain categorized into intrinsically disordered proteins (IDPs) [18][19][20][21][22] . Loss of function of human PQBP1 by mutations causes intellectual disability and microcephaly [23][24][25][26] .…”

mentioning

confidence: 99%

Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation

et al. 2021

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Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.

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“…It is predominantly localized in the cell nucleus, where it forms subnuclear inclusion bodies (Okazawa et al, 2001;Kunde et al, 2011). PQBP1 is functionally related to pre-mRNA splicing and transcription and, more recently, was reported to be involved in innate immune signaling (Waragai et al, 1999(Waragai et al, , 2000Okazawa et al, 2002;Wang et al, 2013;Yoh et al, 2015;Mizuguchi et al, 2016). Sequence alignment of AtWWP1 and PQBP1 revealed a conserved region comprising the first WW domain of AtWWP1 and a highly conserved C-terminal motif (Supplemental Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

A WW Domain-Containing Protein Forms Immune Nuclear Bodies against Begomoviruses

et al. 2018

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The bipartite begomoviruses (Geminiviridae family), which are DNA viruses that replicate in the nucleus of infected cells, encode the nuclear shuttle protein (NSP) to facilitate the translocation of viral DNA from the nucleus to the cytoplasm via nuclear pores. This intracellular trafficking of NSP-DNA complexes is accessorized by the NSP-interacting guanosine triphosphatase (NIG) at the cytosolic side. Here, we report the nuclear redistribution of NIG by AtWWP1, a WW domain-containing protein that forms immune nuclear bodies (NBs) against begomoviruses. We demonstrated that AtWWP1 relocates NIG from the cytoplasm to the nucleus where it is confined to AtWWP1-NBs, suggesting that the NIG-AtWWP1 interaction may interfere with the NIG pro-viral function associated with its cytosolic localization. Consistent with this assumption, loss of AtWWP1 function cuased plants more susceptible to begomovirus infection, whereas overexpression of AtWWP1 enhanced plant resistance to begomovirus. Furthermore, we found that a mutant version of AtWWP1 defective for NB formation was no longer capable of interacting with and relocating NIG to the nucleus and lost its immune function against begomovirus. The antiviral function of AtWWP1-NBs, however, could be antagonized by viral infection that induced either the disruption or a decrease in the number of AtWWP1-NBs. Collectively, these results led us to propose that AtWWP1 organizes nuclear structures into nuclear foci, which provide intrinsic immunity against begomovirus infection.

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Allosteric modulation of the binding affinity between PQBP1 and the spliceosomal protein U5‐15kD

Cited by 9 publications

References 40 publications

The Renpenning syndrome–associated protein PQBP1 facilitates the nuclear import of splicing factor TXNL4A through the karyopherin β2 receptor

The Renpenning syndrome–associated protein PQBP1 facilitates the nuclear import of splicing factor TXNL4A through the karyopherin β2 receptor

Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation

A WW Domain-Containing Protein Forms Immune Nuclear Bodies against Begomoviruses

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