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Abstract
The proteasome is responsible for selective degradation of proteins. It exists in mammalian cells under four main subtypes, which differ by the combination of their catalytic subunits: the standard proteasome (β1–β2–β5), the immunoproteasome (β1i–β2i–β5i) and the two intermediate proteasomes (β1–β2–β5i and β1i–β2–β5i). The efficiency of the four proteasome subtypes to degrade ubiquitinated or oxidized proteins remains unclear. Using cells expressing exclusively one proteasome subtype, we observed that ubiquitinated p21 and c-myc were degraded at similar rates, indicating that the four 26S proteasomes degrade ubiquitinated proteins equally well. Under oxidative stress, we observed a partial dissociation of 26S into 20S proteasomes, which can degrade non-ubiquitinated oxidized proteins. Oxidized calmodulin and hemoglobin were best degraded in vitro by the three β5i-containing 20S proteasomes, while their native forms were not degraded. Circular dichroism analyses indicated that ubiquitin-independent recognition of oxidized proteins by 20S proteasomes was triggered by the disruption of their structure. Accordingly, β5i-containing 20S proteasomes degraded unoxidized naturally disordered protein tau, while 26S proteasomes did not. Our results suggest that the three β5i-containing 20S proteasomes, namely the immunoproteasome and the two intermediate proteasomes, might help cells to eliminate proteins containing disordered domains, including those induced by oxidative stress.
Highlights
The proteasome is responsible for selective degradation of proteins
In immune cells and in cells exposed to inflammatory cytokines, these three catalytic subunits are replaced by their inducible counterparts β1i (PSMB9, LMP2), β2i (PSMB10, MECL1) and β5i (PSMB8, LMP7), forming a second subtype of proteasome called the immunoproteasome (IP)[5]
Because these cell lines have the same background and only differ in their composition of proteasome catalytic subunits, they are ideally suited to compare the intracellular degradation of ubiquitinated proteins by 26S standard proteasome (SP), IP and intermediate proteasomes
Summary
The proteasome is responsible for selective degradation of proteins. It exists in mammalian cells under four main subtypes, which differ by the combination of their catalytic subunits: the standard proteasome (β1–β2–β5), the immunoproteasome (β1i–β2i–β5i) and the two intermediate proteasomes (β1–β2–β5i and β1i–β2–β5i). The two identical outer rings are composed of α1–α7 subunits and form the gate, which regulates the entry of intracellular proteins inside the catalytic chamber of the 20S proteasome. The different proteasome subtypes are found either as free 20S particles or associated with regulatory particles (RP) that interact with the N-terminal tails of the α-subunits to facilitate opening of the gate[7]. These RP include PA28αβ (or 11S RP), PA28γ, PA200 and the 19S RP (or PA700), which associates with 20S proteasomes to form 26S proteasomes, which operate the ATP- and ubiquitin-dependent degradation of intracellular proteins. This step is followed by conformational modifications that favor translocation of the protein substrate coupled with its unfolding, deubiquitination and the opening of the proteasome gate[8,9,10,11]
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