The role of ubiquitination in spinal and bulbar muscular atrophy

Sengupta, Medha; Pluciennik, Anna; Merry, Diane E.

doi:10.3389/fnmol.2022.1020143

Cited by 8 publications

(8 citation statements)

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“…Of the many candidate E3 ligases for AR ubiquitination, the COOH terminus of the Hsp70‐interacting protein (CHIP) also known as STUB1 E3 ubiquitin ligase has been shown to catalyze AR ubiquitination and degradation 7,8 . The role of AR ubiquitination in spinal and bulbar muscular atrophy, a neurodegenerative and neuromuscular genetic disease, caused by the expansion of a polyglutamine‐encoding CAG in the AR gene is well known 9 . As well, the regulation of AR ubiquitination by the heat shock proteins in castration‐resistant prostate cancer is well established 10 .…”

Section: Introductionmentioning

confidence: 99%

“…7,8 The role of AR ubiquitination in spinal and bulbar muscular atrophy, a neurodegenerative and neuromuscular genetic disease, caused by the expansion of a polyglutamine-encoding CAG in the AR gene is well known. 9 As well, the regulation of AR ubiquitination by the heat shock proteins in castration-resistant prostate cancer is well established. 10 Expanding our understanding of the molecular mechanisms regulating AR ubiquitination and degradation and how these mechanisms are dysregulated in the development of male gonad and external genitalia is fundamentally important and clinically relevant.…”

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confidence: 99%

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Regulation of androgen receptor stability by the β₁Pix/STUB1 complex

Chahdi,

Jorgez,

Seth

2024

The FASEB Journal

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The androgen receptor (AR) is essential in the development and differentiation of testes and male genitalia. AR expression is tightly regulated at the translational and posttranslational levels. AR posttranscriptional regulation is a major determinant of AR availability since AR is a direct target of E3 ubiquitin ligase STUB1. Our work indicated that the Rac/Cdc42 guanosine triphosphatase guanine nucleotide exchange factor, β1Pix, enhanced AR levels after AR stimulation in HEK293 and HeLa cells. AR stimulation decreased AR ubiquitination which is accompanied by increased β1Pix binding to AR. Ectopic expression of β1Pix decreased AR ubiquitination in Tm4 and HEK293 cells. We demonstrated that the formation of a multimolecular complex comprised of AR/β1Pix/STUB1 responded in a time‐dependent manner to AR stimulation. β1Pix binding dissociated STUB1 from AR and thus prevented STUB1 from catalyzing receptor ubiquitination. β1Pix enhanced AR transcriptional activity and increased AR target gene expression. Irrespective of treatment, immunofluorescence analysis showed a strong nuclear colocalization of endogenous AR and endogenous βPix in Tm4 cells. However, using Tm4 cell fractionation, AR stimulation decreased βPix/AR association in the cytosolic fraction and increased binding of AR to βPix in the nuclear fraction. To support the role of β1Pix in androgen regulation, we found that individuals lacking this gene have a significant increase in genitourinary malformations associated with androgen dysfunction. Our data indicate that β1Pix is an important modulator of AR stability and ligand‐dependent AR transcriptional activity. We propose that β1Pix could serve as a promising therapeutic target to modulate AR signaling.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Regulation of androgen receptor stability by the β₁Pix/STUB1 complex

Chahdi,

Jorgez,

Seth

2024

The FASEB Journal

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“…HAP1 also seems to be involved in the neuropathology of SBMA, a neurodegenerative and neuromuscular genetic disease characterized by progressive proximal (bulbar and limb) muscle atrophy, weakness and fasciculations, that is caused by the expansion of a polyQ-encoding CAG tract in the AR gene ( Takeshita et al, 2006 ; Sengupta et al, 2022 ). HAP1 can interact with AR through its ligand-binding domain in a polyQ-length-dependent manner and protect cells from polyQ-expanded AR-induced apoptosis by sequestering polyQ-expanded AR in STBs ( Takeshita et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

Huntingtin-associated protein 1-associated intracellular trafficking in neurodegenerative diseases

Chen

et al. 2023

Front. Aging Neurosci.

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Huntingtin-associated protein 1 (HAP1), the first identified HTT-binding partner, is highly expressed in the central nervous system, and has been found to associated with neurological diseases. Mounting evidence suggests that HAP1 functions as a component of cargo-motor molecules to bind various proteins and participates in intracellular trafficking. It is known that the failure of intracellular transport is a key contributor to the progression of neurodegenerative disorders (NDs) including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), spinal and bulbar muscular atrophy (SBMA) and spinocerebellar ataxia (SCA). The link between HAP1 and various NDs is supported by growing evidence. This review aims to provide a comprehensive overview of the intracellular trafficking function of HAP1 and its involvement in NDs.

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“…Within the nucleus, it dimerizes, binds to androgen-response elements (AREs) on DNA, and facilitates the transcription of androgen-responsive genes. Both ligand-binding and subsequent nuclear translocation are implicated in SBMA pathogenesis 6,[33][34][35][36] .…”

Section: Introductionmentioning

confidence: 99%

A phenotypically robust model of Spinal and Bulbar Muscular Atrophy inDrosophila

Richardson

Sengupta

Sujkowski

et al. 2023

Preprint

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Spinal and bulbar muscular atrophy (SBMA) is an X-linked disorder that affects males who inherit the androgen receptor (AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen-dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA in Drosophila melanogaster. We generated transgenic flies that express the full-length, human AR with a wild-type or pathogenic polyQ repeat. Each transgene is inserted into the same safe harbor site on the third chromosome of the fly as a single copy and in the same orientation. Expression of pathogenic AR, but not of its wild-type variant, in neurons or muscles leads to consistent, progressive defects in longevity and motility that are concomitant with polyQ-expanded AR protein aggregation and reduced complexity in neuromuscular junctions. Additional assays show adult fly eye abnormalities associated with the pathogenic AR species. The detrimental effects of pathogenic AR are accentuated by feeding flies the androgen, dihydrotestosterone. This new, robust SBMA model can be a valuable tool towards future investigations of this incurable disease.

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The role of ubiquitination in spinal and bulbar muscular atrophy

Cited by 8 publications

References 295 publications

Regulation of androgen receptor stability by the β₁Pix/STUB1 complex

Regulation of androgen receptor stability by the β₁Pix/STUB1 complex

Huntingtin-associated protein 1-associated intracellular trafficking in neurodegenerative diseases

A phenotypically robust model of Spinal and Bulbar Muscular Atrophy inDrosophila

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The role of ubiquitination in spinal and bulbar muscular atrophy

Cited by 8 publications

References 295 publications

Regulation of androgen receptor stability by the β1Pix/STUB1 complex

Regulation of androgen receptor stability by the β1Pix/STUB1 complex

Huntingtin-associated protein 1-associated intracellular trafficking in neurodegenerative diseases

A phenotypically robust model of Spinal and Bulbar Muscular Atrophy inDrosophila

Contact Info

Product

Resources

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Regulation of androgen receptor stability by the β₁Pix/STUB1 complex

Regulation of androgen receptor stability by the β₁Pix/STUB1 complex