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 found an evolutionarily conserved signalling pathway controlling proteasome homeostasis. Central to this pathway is TORC1 whose inhibition 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, ensured that the supply of RACs and proteasome subunits increased under challenging conditions 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 to the rising needs. Enhancing this pathway may be a useful therapeutic approach for diseases resulting from impaired proteasomal degradation.