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