Transcriptional regulatory networks of the proteasome in mammalian systems

Abstract

The tight regulation of proteostasis is essential for physiological cellular function. Mammalian cells possess a network of mechanisms that ensure proteome integrity under normal or stress conditions. The proteasome, being the major cellular proteolytic machinery, is central to proteostasis maintenance in response to distinct intracellular and extracellular conditions. The proteasomes are multisubunit protease complexes that selectively catalyze the degradation of short-lived regulatory proteins and damaged peptides. Different forms of the proteasome complexes comprising of different subunits and attached regulators directly affect the substrate selectivity and degradation. Thus, the proteasome participates in the turnover of a multitude of factors that control key processes that affect the cellular state, such as adaptation to environmental cues, growth, development, metabolism, signaling, senescence, pluripotency, differentiation, and immunity. Aberrations on its function are related to normal processes like aging and pathological conditions such as neurodegeneration and cancer. The past few years of research have highlighted that proteasome abundance, activity, assembly, and localization are subject to a dynamic transcriptional control that secures the continuous adaptation of the proteasome to internal or external stimuli. This review focuses on the factors and signaling pathways that are involved in the regulation of the mammalian proteasome at the transcriptional level. A comprehensive understanding of proteasome regulation has critical implications on disease prevention and treatment.