An evolutionarily conserved pathway controls proteasome homeostasis

Proteasome abundance is crucial for cell survival, but how cells maintain adequate amounts of proteasome is unclear; an analysis in yeast identifies TORC1 and Mpk1 as central components of a pathway regulating proteasome homeostasis through the coordinated regulation of regulatory particle assembly chaperones and proteasome subunits—this pathway is evolutionarily conserved with mTOR and ERK5 regulating proteasome abundance in mammals. Keeping the proteasome under control The proteasome is the cell's protein degradation machinery. It is composed of a core particle and two regulatory particles. Chaperone proteins known as RACs mediate the assembly of the regulatory particles, and under stressful conditions in yeast, an additional chaperone called Adc17 helps to generate more proteasomes. A long-standing question has been how stress leads to increased Adc17 levels. Adrien Rousseau and Anne Bertolotti report that an evolutionarily conserved signalling pathway controls proteasome homeostasis in yeast and mammals. Specifically, they find that in an adaptive response to stress, the TORC1 protein in yeast (mTOR in mammals) is inhibited. Consequently, the downstream signalling molecule — the enzyme Mpk1 in yeast or Erk5 in mammals — ensures increased supplies of not just RACs, but also proteasome subunits. 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.