Nature of the nuclear inclusions formed by PQBP1, a protein linked to neurodegenerative polyglutamine diseases

Nicolaescu, Emilia; Beullens, Monique; Lesage, Bart; Keppens, Stefaan; Himpens, Bernard

doi:10.1016/j.ejcb.2008.05.001

Cited by 7 publications

(6 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…the co-expression of pqbp1 and wbp11 in the same tissues of Xenopus embryos is consistent with the known physical and functional links between the two proteins (Komuro et al, 1999b;Llorian et al, 2004Llorian et al, , 2005Nicolaescu et al, 2008). Whether these proteins function together mechanistically to govern the same biochemical or embryonic processes remains to be determined.…”

Section: Pqbp1 and Wbp11 Are Required For Normal Mesodermal And Neurasupporting

confidence: 52%

“…The spliceosome protein WBP11 is an endogenous partner of mammalian PQBP1 (Nicolaescu et al, 2008;Tapia et al, 2010), but despite its functional importance in pre-mRNA splicing, nothing is known about its developmental expression or function. We identified two homeologs in X. laevis that encode predicted proteins with 95% (604/636) identity to each other and 74% identity to human WBP11 (supplementary material Fig.…”

Section: Wbp11 Is Essential For Normal Developmentmentioning

confidence: 99%

“…A missense mutation within the WW domain at the N-terminus of PQBP1 in Golabi-Ito-Hall (GIH) patients (Y65C) causes abnormal pre-mRNA splicing and inhibits PQBP1 binding to spliceosome components and a partner protein, WBP11 (Lubs et al, 2006;Tapia et al, 2010;Sudol et al, 2012). PQBP1 and WBP11 both associate with the BΔU1 or PRP19 spliceosomal complexes (Makarova et al, 2004;Deckert et al, 2006) and colocalize to nuclear speckles enriched in splicing factors (Komuro et al, 1999b;Llorian et al, 2004Llorian et al, , 2005Nicolaescu et al, 2008). A central, polar amino acid-rich domain (PRD) in mammalian PQBP1 can bind to proteins with polyglutamine ( polyQ) tracts, such as transcription factors Brn2 and Ataxin-1, and the cytoplasmic transport protein Huntingtin (Htt), which is enhanced in poly(Q)-expanded pathogenic mutants of these human proteins (Waragai et al, 1999;Okazawa et al, 2002;Busch et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

Iwasaki

Thomsen

2014

Development

View full text Add to dashboard Cite

Alternative splicing of pre-mRNAs is an important means of regulating developmental processes, yet the molecular mechanisms governing alternative splicing in embryonic contexts are just beginning to emerge. Polyglutamine-binding protein 1 (PQBP1) is an RNAsplicing factor that, when mutated, in humans causes Renpenning syndrome, an X-linked intellectual disability disease characterized by severe cognitive impairment, but also by physical defects that suggest PQBP1 has broader functions in embryonic development. Here, we reveal essential roles for PQBP1 and a binding partner, WBP11, in early development of Xenopus embryos. Both genes are expressed in the nascent mesoderm and neurectoderm, and morpholino knockdown of either causes defects in differentiation and morphogenesis of the mesoderm and neural plate. At the molecular level, knockdown of PQBP1 in Xenopus animal cap explants inhibits target gene induction by FGF but not by BMP, Nodal or Wnt ligands, and knockdown of either PQBP1 or WBP11 in embryos inhibits expression of fgf4 and FGF4-responsive cdx4 genes. Furthermore, PQBP1 knockdown changes the alternative splicing of FGF receptor-2 (FGFR2) transcripts, altering the incorporation of cassette exons that generate receptor variants (FGFR2 IIIb or IIIc) with different ligand specificities. Our findings may inform studies into the mechanisms underlying Renpenning syndrome.

show abstract

Section: Pqbp1 and Wbp11 Are Required For Normal Mesodermal And Neurasupporting

confidence: 52%

Section: Wbp11 Is Essential For Normal Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

Iwasaki

Thomsen

2014

Development

View full text Add to dashboard Cite

show abstract

“…PQBP1 is dominantly localized in nuclei (6,8,29,30). Previous reports show that PQBP1 contains a PY nuclear localization signal (PY-NLS) and is a substrate of nuclear import receptor karyopherin β2 (Kapβ2) (13).…”

Section: Pqbp1 Contains a Py-nls Recognized By Kapβ2mentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…WW Domain-Because, in contrast to Atrophin 1, WBP11 protein was implicated in the function of PQBP1 (42) and the proline-rich peptide used in the ITC study was arbitrarily selected from a long proline-rich region of WBP11 with many potential, overlapping WW domain binding motifs, we decided to use a longer proline-rich polypeptide and perform a SPR binding assay with WW domains. The 38-amino acid long human WBP11 peptide ( 429 GLPPGPPPGAPPFLRPPGMPGL-RGPLPRLLPPGPPPGR 466 ) was modified at the N-terminal region with three lysine and one ␤-alanine residues for oriented binding.…”

Section: Spr Analysis Suggests a Loss Of Function For The Y65c Mutantmentioning

confidence: 99%

Y65C Missense Mutation in the WW Domain of the Golabi-Ito-Hall Syndrome Protein PQBP1 Affects Its Binding Activity and Deregulates Pre-mRNA Splicing

Tapia

Nicolaescu

McDonald

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The PQBP1 (polyglutamine tract-binding protein 1) gene encodes a nuclear protein that regulates pre-mRNA splicing and transcription. Mutations in the PQBP1 gene were reported in several X chromosome-linked mental retardation disorders including Golabi-Ito-Hall syndrome. The missense mutation that causes this syndrome is unique among other PQBP1 mutations reported to date because it maps within a functional domain of PQBP1, known as the WW domain. The mutation substitutes tyrosine 65 with cysteine and is located within the conserved core of aromatic amino acids of the domain. We show here that the binding property of the Y65C-mutated WW domain and the full-length mutant protein toward its cognate proline-rich ligands was diminished. Furthermore, in GolabiIto-Hall-derived lymphoblasts we showed that the complex between PQBP1-Y65C and WBP11 (WW domain-binding protein 11) splicing factor was compromised. In these cells a substantial decrease in pre-mRNA splicing efficiency was detected. Our study points to the critical role of the WW domain in the function of the PQBP1 protein and provides an insight into the molecular mechanism that underlies the X chromosome-linked mental retardation entities classified globally as Renpenning syndrome.

show abstract

Nature of the nuclear inclusions formed by PQBP1, a protein linked to neurodegenerative polyglutamine diseases

Cited by 7 publications

References 22 publications

The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

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

Y65C Missense Mutation in the WW Domain of the Golabi-Ito-Hall Syndrome Protein PQBP1 Affects Its Binding Activity and Deregulates Pre-mRNA Splicing

Contact Info

Product

Resources

About