Abstract
Maintaining 26S proteasome activity under diverse physiological conditions is a fundamental requirement in order to maintain cellular proteostasis. Several quantitative and qualitative mechanisms have evolved to ensure that ubiquitin–proteasome system (UPS) substrates do not accumulate and lead to promiscuous protein–protein interactions that, in turn, lead to cellular malfunction. In this report, we demonstrate that Arsenite Inducible Regulatory Particle-Associate Protein (AIRAP), previously reported as a proteasomal adaptor required for maintaining proteasomal flux during arsenite exposure, can directly bind arsenite molecules. We further show that arsenite inhibits Psmd14/Rpn11 metalloprotease deubiquitination activity by substituting zinc binding to the MPN/JAMM domain. The proteasomal adaptor AIRAP is able to directly relieve PSMD14/Rpn11 inhibition. A possible metal relay between arsenylated PSMD14/Rpn11 and AIRAP may serve as a cellular mechanism that senses proteasomal inhibition to restore Psmd14/Rpn11 activity.
Highlights
IntroductionWe can artificially divide these modifications into several categories, including quantitative and qualitative changes in proteasome subunits (executed by transcriptional [3,4,5] and translational [6] programs as well as posttranslational modifications of proteasome subunits [7]) and changes in the composition of specific subunits, as exemplified in the case of the immunoproteasome (20Si) and the thymus proteasome (20St)
Promiscuous interactions of misfolded proteins are highly toxic to the cell and manifest in various pathologies [1]; restoring the proper configuration of misfolded proteins by chaperones, reducing enzymes and more constitutes a salvation pathway. Degradation pathways such as the ubiquitin–proteasome system (UPS) or the lysosomal pathway eliminate the toxicity of misfolded proteins by proteolytic degradation [2]
To evaluate the the possibility of the direct binding of to arsenite, we utilized an immobilized possibility of the direct binding of Arsenite Inducible Regulatory Particle-Associate Protein (AIRAP) to arsenite, we utilized an immobilized bivalent bivalent form of (phenylarsine arsenite (phenylarsine oxidepreviously (PAO)) previously demonstrated to bind form of arsenite oxide (PAO))
Summary
We can artificially divide these modifications into several categories, including quantitative and qualitative changes in proteasome subunits (executed by transcriptional [3,4,5] and translational [6] programs as well as posttranslational modifications of proteasome subunits [7]) and changes in the composition of specific subunits, as exemplified in the case of the immunoproteasome (20Si) and the thymus proteasome (20St) In this mode of regulation, the exchange of catalytic subunits in response to acute signaling (IFN-γ) [8,9] or unique surroundings [10,11] enables modification of the proteasome to a more suitable peptide output. Alternative caps such as PA200 enable the engagement of the proteasome with specific substrates [12,13], while the PA28 (11S)
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