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Updated: Mar 17, 2026
Quantifying Tissue-Specific Proteostatic Decline in Caenorhabditis elegans
Published on: September 7, 2021
An evolutionarily conserved pathway controls proteasome homeostasis
Abstract:
The proteasome is essential for the selective degradation of most cellular proteins, but how cells maintain adequate amounts of proteasome is unclear. Here we show that there is an evolutionarily conserved signalling pathway controlling proteasome homeostasis. Central to this pathway is TORC1, the inhibition of which induced all known yeast 19S regulatory particle assembly-chaperones (RACs), as well as proteasome subunits. Downstream of TORC1 inhibition, the yeast mitogen-activated protein kinase, Mpk1, acts to increase the supply of RACs and proteasome subunits under challenging conditions in order to maintain proteasomal degradation and cell viability. This adaptive pathway was evolutionarily conserved, with mTOR and ERK5 controlling the levels of the four mammalian RACs and proteasome abundance. Thus, the central growth and stress controllers, TORC1 and Mpk1/ERK5, endow cells with a rapid and vital adaptive response to adjust proteasome abundance in response to the rising needs of cells. Enhancing this pathway may be a useful therapeutic approach for diseases resulting from impaired proteasomal degradation.
Insights
A conserved signaling pathway regulates proteasome levels. Inhibiting TORC1 activates Mpk1, increasing proteasome components for cell survival under stress. This pathway is conserved in mammals.
Area of Science:
- Cellular biology
- Molecular biology
- Biochemistry
Background:
- The proteasome is crucial for protein degradation, yet mechanisms maintaining its abundance (proteasome homeostasis) are not fully understood.
- Cellular proteasome levels must be tightly regulated to meet cellular demands for protein turnover.
Purpose of the Study:
- To elucidate the signaling pathways governing proteasome homeostasis.
- To identify key regulators controlling proteasome subunit and assembly chaperone production.
Main Methods:
- Yeast genetics and molecular biology techniques were employed to study the role of TORC1 and Mpk1.
- Mammalian cell culture and molecular analyses were used to assess evolutionary conservation.
Main Results:
- Inhibition of TORC1 (target of rapamycin complex 1) in yeast induced the expression of 19S regulatory particle assembly-chaperones (RACs) and proteasome subunits.
- Downstream of TORC1, the Mpk1 (mitogen-activated protein kinase) pathway was activated, increasing RACs and proteasome subunits, thereby maintaining proteasomal degradation and cell viability under stress.
- The pathway involving mTOR (mammalian TOR) and ERK5 (extracellular signal-regulated kinase 5) was found to be conserved in mammals, controlling RAC levels and proteasome abundance.
Conclusions:
- A conserved signaling pathway, involving TORC1/mTOR and Mpk1/ERK5, rapidly adjusts proteasome abundance in response to cellular needs and stress.
- This adaptive response is vital for maintaining proteasomal degradation and cell viability.
- Targeting this pathway presents a potential therapeutic strategy for diseases characterized by impaired proteasomal degradation.
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