The Ubiquitin-Conjugating Enzyme UBE2D/eff Maintains Protein Quality Control and a Youthful Proteome Composition During Aging

Kernkonzepte

The ubiquitin-conjugating enzyme UBE2D/eff is necessary to maintain protein quality control and a youthful proteome composition in skeletal muscle during aging.

Zusammenfassung

This study examines the role of the 21 Drosophila E2 ubiquitin-conjugating enzymes in regulating the aggregation of a model polyglutamine protein, huntingtin-polyQ. The findings reveal diverse functions of E2s, with some promoting and others inhibiting huntingtin-polyQ aggregation.
Specifically, the E2 enzyme UBE2D/eff (homologous to human UBE2D1/2/3/4) is found to be crucial for protein quality control. UBE2D/eff levels decline during aging in Drosophila skeletal muscle, and experimentally inducing UBE2D/eff knockdown from a young age causes a premature accumulation of insoluble poly-ubiquitinated proteins, which normally occurs only in old age.
Proteomics analyses indicate that UBE2D/eff knockdown rewires the muscle proteome in a manner similar to natural aging, and that these changes are partially rescued by the expression of the human UBE2D2 homolog. Further, muscle-specific UBE2D/eff knockdown reduces organismal lifespan, which is also rescued by UBE2D2.
Altogether, these findings identify UBE2D/eff as a key regulator of proteostasis and proteome composition during aging, highlighting its evolutionary-conserved role in maintaining a youthful proteome and ensuring protein quality control.

Statistiken

UBE2D/eff protein levels significantly decline during aging in Drosophila skeletal muscle.
Knockdown of UBE2D/eff in young muscle increases the accumulation of insoluble poly-ubiquitinated proteins.
Proteomics analysis reveals that UBE2D/eff knockdown induces proteomic changes that overlap extensively with those occurring during natural aging.
Muscle-specific knockdown of UBE2D/eff reduces organismal lifespan, which is partially rescued by expression of the human UBE2D2 homolog.

Zitate

"UBE2D/eff is necessary to maintain a youthful proteome and that the age-dependent decline in UBE2D/eff protein levels may contribute to the proteomic changes that occur with aging."
"Altogether, these findings reinforce the notion that skeletal muscle is a key tissue that influences systemic aging, and that preserving muscle protein quality control is necessary for optimal organismal survival."

Wichtige Erkenntnisse aus

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

by Hunt,L. C., ... um www.biorxiv.org 12-13-2023

https://www.biorxiv.org/content/10.1101/2023.12.12.571303v2

Tiefere Fragen

What other cellular processes or pathways might be impacted by the age-dependent decline in UBE2D/eff levels, beyond proteostasis?

The age-dependent decline in UBE2D/eff levels could impact various cellular processes and pathways beyond proteostasis. One significant area that could be affected is DNA repair and maintenance. UBE2D/eff has been shown to interact with E3 ligases involved in DNA repair processes, such as RNF138, suggesting a role in maintaining genomic stability. Therefore, reduced UBE2D/eff levels with aging may compromise DNA repair efficiency, leading to an accumulation of DNA damage and genomic instability.
Additionally, UBE2D/eff is involved in mitophagy, the process of clearing damaged mitochondria, which is crucial for cellular homeostasis. A decline in UBE2D/eff levels could impair mitophagy, leading to the accumulation of dysfunctional mitochondria and increased oxidative stress. This, in turn, could impact cellular energy production, signaling pathways, and overall cellular health.
Furthermore, UBE2D/eff is known to play a role in protein import into peroxisomes, organelles involved in lipid metabolism and detoxification. Reduced UBE2D/eff levels may disrupt peroxisomal function, affecting lipid metabolism and cellular detoxification processes. This could have implications for cellular lipid homeostasis, energy balance, and response to oxidative stress.

How might the accumulation of specific UBE2D/eff substrates, such as Arc1/2, contribute to the derangement of proteostasis and reduced lifespan observed upon UBE2D/eff knockdown?

The accumulation of specific UBE2D/eff substrates, such as Arc1/2, could contribute to the derangement of proteostasis and reduced lifespan observed upon UBE2D/eff knockdown through multiple mechanisms. Arc1 and Arc2 proteins have been implicated in cytotoxicity and neurodegeneration, suggesting that their accumulation could lead to cellular dysfunction and damage.
One way in which the accumulation of Arc1/2 could impact proteostasis is by interfering with the degradation of misfolded or damaged proteins. UBE2D/eff is involved in the ubiquitination and targeting of proteins for degradation, including misfolded or aggregated proteins. The accumulation of Arc1/2 may compete for ubiquitination and proteasomal degradation, leading to the buildup of toxic protein aggregates and impaired proteostasis.
Moreover, Arc1/2 proteins may disrupt cellular signaling pathways and protein interactions essential for maintaining cellular homeostasis. Their aberrant accumulation could interfere with normal cellular processes, such as synaptic function, metabolism, and stress response, further contributing to proteostasis dysfunction and cellular damage.
Overall, the accumulation of specific UBE2D/eff substrates like Arc1/2 could disrupt multiple cellular pathways, leading to proteostasis derangement, cellular dysfunction, and ultimately reduced lifespan upon UBE2D/eff knockdown.

Could pharmacological or genetic strategies that enhance UBE2D/eff function be explored as interventions to maintain proteostasis and delay age-related diseases?

Exploring pharmacological or genetic strategies to enhance UBE2D/eff function could indeed be a promising approach to maintain proteostasis and delay age-related diseases. One potential strategy could involve the development of small molecule activators or stabilizers of UBE2D/eff enzyme activity. These compounds could enhance the ubiquitination and degradation of misfolded or damaged proteins, promoting protein quality control and preventing the accumulation of toxic aggregates.
Another approach could be gene therapy or gene editing techniques to increase UBE2D/eff expression or activity in specific tissues or cell types. By upregulating UBE2D/eff levels, cellular proteostasis could be improved, leading to better protein turnover and reduced accumulation of protein aggregates associated with aging and age-related diseases.
Furthermore, targeting pathways that regulate UBE2D/eff expression or activity could also be explored. Modulating signaling pathways or transcription factors that control UBE2D/eff levels could provide a more targeted and specific way to enhance protein quality control and maintain cellular homeostasis.
Overall, investigating pharmacological or genetic strategies to enhance UBE2D/eff function holds promise for developing interventions that could help maintain proteostasis, delay age-related diseases, and promote healthy aging.