Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging

Jiao, Jianqin; Curley, Michelle; Graça, Flávia A.; Robles-Murguia, Maricela; Shirinifard, Abbas; Finkelstein, David; Xu, Beisi; Fan, Yiping; Demontis, Fabio

doi:10.1016/j.celrep.2022.111970

Cited by 6 publications

(4 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that knocking down Ptx1 (Supplementary Fig. 12a ), the Drosophila orthologue of human PITX2 45 , in vivo rescued the climbing and survival defects in disease flies (Fig. 7f, g ).…”

Section: Resultsmentioning

confidence: 88%

Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD

Chen,

Ou,

Taylor

et al. 2023

Nat Commun

View full text Add to dashboard Cite

The GGGGCC hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C9orf72) gene is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). In this study, we demonstrate that the zinc finger (ZF) transcriptional regulator Yin Yang 1 (YY1) binds to the promoter region of the planar cell polarity gene Fuzzy to regulate its transcription. We show that YY1 interacts with GGGGCC repeat RNA via its ZF and that this interaction compromises the binding of YY1 to the FuzzyYY1 promoter sites, resulting in the downregulation of Fuzzy transcription. The decrease in Fuzzy protein expression in turn activates the canonical Wnt/β-catenin pathway and induces synaptic deficits in C9ALS/FTD neurons. Our findings demonstrate a C9orf72 GGGGCC RNA-initiated perturbation of YY1–Fuzzy transcriptional control that implicates aberrant Wnt/β-catenin signalling in C9ALS/FTD-associated neurodegeneration. This pathogenic cascade provides a potential new target for disease-modifying therapy.

show abstract

“…We found that knocking down Ptx1 (Supplementary Fig. 12a ), the Drosophila orthologue of human PITX2 45 , in vivo rescued the climbing and survival defects in disease flies (Fig. 7f, g ).…”

Section: Resultsmentioning

confidence: 88%

Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD

Chen,

Ou,

Taylor

et al. 2023

Nat Commun

View full text Add to dashboard Cite

show abstract

“…Because muscle proteostasis has been found to regulate organismal aging ( 25, 47, 49, 57, 58 ), we next determined the impact of muscle-specific UBE2D/eff loss on lifespan. Knockdown of eff with 2 distinct RNAi lines (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To this purpose, we examined skeletal muscle aging, which is characterized by a progressive decline in proteostasis and by the age-related accumulation of detergent-insoluble poly-ubiquitin protein aggregates (25,(47)(48)(49)(50)(51)(52)(53).…”

Section: Ube2d/eff Protein Levels Decline With Aging and Ube2d/eff Kn...mentioning

confidence: 99%

The ubiquitin-conjugating enzyme UBE2D/eff maintains a youthful proteome and ensures protein quality control during aging

Hunt,

Nyamkondiwa,

Stephan

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

SUMMARYUbiquitin-conjugating enzymes (E2s) are key for regulating protein function and turnover via ubiquitination but it remains undetermined which E2s maintain proteostasis during aging. Here, we find that E2s have diverse roles in handling a model aggregation-prone protein (huntingtin-polyQ) in theDrosophilaretina: while some E2s mediate aggregate assembly, UBE2D/effete (eff) and other E2s are required for huntingtin-polyQ degradation. UBE2D/eff is key for proteostasis also in skeletal muscle: eff protein levels decline with aging, and muscle-specific eff knockdown causes an accelerated buildup in insoluble poly-ubiquitinated proteins (which progressively accumulate with aging) and shortens lifespan. Transgenic expression of human UBE2D2, homologous to eff, partially rescues the lifespan and proteostasis deficits caused by muscle-specific effRNAiby re-establishing the physiological levels of effRNAi-regulated proteins. Interestingly, UBE2D/eff knockdown in young age reproduces many of the proteomic changes that normally occur in old muscles, suggesting that the decrease in UBE2D/eff protein levels that occurs with aging contributes to reshaping the composition of the muscle proteome. Altogether, these findings indicate that UBE2D/eff is a key E2 ubiquitin-conjugating enzyme for maintaining a youthful proteome and for ensuring protein quality control during aging.

show abstract

“…UPS controls fast and efficient elimination of unfolded or misfolded proteins [15], thereby orchestrating crucial cellular functions, including cell cycle control [16,17] and cell fate determination [18]. Accordingly, dysregulation on the UPS is associated with aging as well as pathologic conditions, including neurodegenerative diseases and cancer [19][20][21]. Major experts in the field have previously reviewed the biochemical mechanisms of UPS components and interactors [22].…”

Section: Fundamentals Of Targeted Protein Degradationmentioning

confidence: 99%

PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas

Mancarella,

Morrione,

Scotlandi

2023

IJMS

View full text Add to dashboard Cite

Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling discovered more than 100 subtypes, which are characterized by peculiar molecular vulnerabilities. However, limited therapeutic options exist beyond standard therapy and clinical benefits from targeted therapies were observed only in a minority of patients with sarcomas. The rarity of these tumors, paucity of actionable mutations, and limitations in the chemical composition of current targeted therapies hindered the use of these approaches in sarcomas. Targeted protein degradation (TPD) is an innovative pharmacological modality to directly alter protein abundance with promising clinical potential in cancer, even for undruggable proteins. TPD is based on the use of small molecules called degraders or proteolysis-targeting chimeras (PROTACs), which trigger ubiquitin-dependent degradation of protein of interest. In this review, we will discuss major features of PROTAC and PROTAC-derived genetic systems for target validation and cancer treatment and focus on the potential of these approaches to overcome major issues connected to targeted therapies in sarcomas, including drug resistance, target specificity, and undruggable targets. A deeper understanding of these strategies might provide new fuel to drive molecular and personalized medicine to sarcomas.

show abstract

Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging

Cited by 6 publications

References 101 publications

Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD

Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD

The ubiquitin-conjugating enzyme UBE2D/eff maintains a youthful proteome and ensures protein quality control during aging

PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas

Contact Info

Product

Resources

About