Adaptation of Proteasomes and Lysosomes to Cellular Environments

Abstract

Protein degradation is important for proper cellular physiology as it removes malfunctioning proteins or can provide a source for energy. Proteasomes and lysosomes, through the regulatory particles or adaptor proteins, respectively, recognize proteins destined for degradation. These systems have developed mechanisms to allow adaptation to the everchanging environment of the cell. While the complex recognition of proteins to be degraded is somewhat understood, the mechanisms that help switch the proteasomal regulatory particles or lysosomal adaptor proteins to adjust to the changing landscape of degrons, during infections or inflammation, still need extensive exploration. Therefore, this review is focused on describing the protein degradation systems and the possible sensors that may trigger the rapid adaptation of the protein degradation machinery.

Keywords: aggresome; autophagy; core particle; endosome; protein degradation; regulatory particle.

Figure 1

Proteasomal components. The proteasome can be divided into the 2 main structures: the 20S core protease (CP) and the 19S regulatory particle (RP). The 20S consists of α and β subunits, with 7 α-subunits forming the α-ring, and 7 β-subunits forming the β-ring. When the immunoproteasome is activated, there are 3 β-subunits that are replaced, β1i for β1, β2i for β2, and β i for β to form the Immunoproteasome. The CP in the thymus is equipped by β5t instead of the β5. The 19S RPs is a protein-complex made out 6 subunits of Rpt and 13 subunits of Rpn proteins important to keep the 20S CP open and to bind and process ubiquitylated proteins for degradation.

Figure 2

Types of Proteasomes. The constitutive proteasome is composed of the 20S CP and a single or double 19S cap to form the 26S or 30S proteasomes, respectively. When cells are exposed to inflammatory stimuli, i.e., TNF-α or IFN-γ, immunoproteasomes are assembled. The 20S CP incorporates βi-Ring, and is capped by PA28α/β, PA28γ, and PA200 caps on either one of both sides. Hybrid proteasomes have a 19S cap mixed with any of the activated caps (PA28α/β, PA28γ, and PA200). Hybrid iProteasome may be comprised of 11S, 20S, and 11S, or 19S cap, 20S, and 11S components. The inducible proteasome is composed of the 20S iProteasome and a single or double 19S cap to form the 19S-20S or 19S-20S-19S proteasomes, respectively.

Figure 3

Autophagy adaptors. Ubiquitin recognition receptors are multiple in nature, but they share common areas that serve to recognize and bind to ubiquitin, and areas that allow recruitment of LC3 for the autophagophore. The receptors depicted are Neighbor of BRCA1 Gene 1 (NBR1), Ubiquitin-Binding Protein P62 (p62), nuclear dot protein 52; also known as calcium binding and coiled-coil domain 2 [CALCOCO2] (NDP52), optineurin (OPTN), Tax1-binding protein 1 (Tax1), Toll-Interacting Protein (TOLLIP), and NIX/BNIP3L [BCL2/adenovirus E1B 19 kDa interacting protein 3-like] (NIX/BNIP3). The ubiquitin binding domains are: ubiquitin-associated domain (UBA), Ubiquitin binding in ABIN and NEMO domain (UBAN), Ubiquitin-binding zinc finger domain (UBZ), Endoplasmic reticulum-associated degradation domain (Cue). The LC3 recruiting domains are: LC3-interacting region (LIR), non-canonical LIR motif (CLIR), and LC3 recognition sequence (LRS).

Figure 4

Adaptation for ubiquitin-dependent and -independent protein degradation. Combinations of proteasomal regulatory particles and autophagy adaptor proteins and possible heat-shock proteins and Bcl-2-associated athanogene proteins that allow adaptation of the protein degradation machinery depending on the cellular needs. Ubiquitylated proteins can be recognized various types of regulatory particles or by adaptive proteins that allow lysosomal degradation. Proteins with a specific recognition motif are either recognized by the chaperone-mediated (CMA) or chaperone-assisted selective (CASA) autophagy mechanisms to guide the cargo into the lysosomal degradation.