Substrate receptors of proteasomes

Abstract

Proteasomes are responsible for the turnover of most cellular proteins, and thus are critical to almost all cellular activities. A substrate entering the proteasome must first bind to a substrate receptor. Substrate receptors can be classified as ubiquitin receptors and non-ubiquitin receptors. The intrinsic ubiquitin receptors, including proteasome regulatory particle base subunits 1, 10 and 13 (Rpn1, Rpn10, and Rpn13), determine the capability of the proteasome to recognize a ubiquitin chain, and thus provide selectivity for the 26S proteasome. However, the non-ubiquitin receptors, including proteasome activator 200 (PA200) and PA28γ, have received great attention due to their remarkable compensatory roles relative to canonical ubiquitin-mediated proteasomal degradation. Herein we review recent advances in understanding the contributions of these substrate receptors to proteasomal degradation, and introduce their substrates and interacting factors. We also provide insights into their biological functions related to spermatogenesis, immune responses, cellular homeostasis, and tumour development. Finally, we summarize advances in developing small-molecule inhibitors of these substrate receptors and discuss their potential as drug targets.

Cryo-EM structures of the human PA200 and PA200-20S complex reveal regulation of proteasome gate opening and two PA200 apertures

“…This regulation is carried out primarily by proteasomes [1][2][3]. Proteasomes are essential multicatalytic proteases located within cytosol and nucleus that degrade various intracellular proteins [4,5]. In mammalian cells, proteasome activators (PAs) form a variety of complexes via binding of the 20S core particle (CP) with one or two activators or regulators belonging to four different types [4,[6][7][8].…”

“…Proteasomes are essential multicatalytic proteases located within cytosol and nucleus that degrade various intracellular proteins [4,5]. In mammalian cells, proteasome activators (PAs) form a variety of complexes via binding of the 20S core particle (CP) with one or two activators or regulators belonging to four different types [4,[6][7][8]. The most broadly conserved type is the eukaryotic 19S activator (regulatory particle/PA700) [9][10][11].…”

“…The proteasomes originating from testicular tissue represent a particular case, with 90% of the proteasomal complexes containing one or two PA200 molecules [17,18]. These non-ATPase activators do not promote general proteolysis of intact globular proteins; instead, they may play a role in a pathway alternative to the canonical proteasome degradation pathway that would allow more efficient protein degradation under certain situations such as metabolic adaptation and stress response [4,15,[19][20][21].…”

Proteasome activator PA200 maintains stability of histone marks during transcription and aging

“…Proteasomes catalyze degradation of most cellular proteins, and consist of a 20S catalytic particle and one or two activators, such as the 19S regulatory particle, PA28/, PA28 and PA200/PSME4 (10,11). The typical 26S proteasome with the 19S particle as the activator promotes the ubiquitin-dependent protein degradation (12).…”

Structural Insight into Regulation of the Proteasome Ub-Receptor Rpn10

“…The 26S proteasome is a multiprotein complex that degrades ubiquitylated proteins. Several proteasome Ub-receptors that mediate the recognition of ubiquitylated proteins were identified including proteasome subunits Rpn1 [2], Rpn10 [3], and Rpn13 [4] and shuttling factors Dsk2, Rad23, and Ddi1 that are not a proteasome subunit [5].…”