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Review
. 2020 Jul;26(7):639-648.
doi: 10.1016/j.molmed.2020.02.007. Epub 2020 Mar 26.

Priming the Proteasome to Protect against Proteotoxicity

Xuejun Wang  1 , Hongmin Wang  2
Affiliations
Review

Priming the Proteasome to Protect against Proteotoxicity

Xuejun Wang et al. Trends Mol Med. 2020 Jul.

Abstract

Increased proteotoxic stress (IPTS) resulting from the increased production or decreased removal of abnormally folded proteins is recognized as an important pathogenic factor for a large group of highly disabling and life-threatening human diseases, such as neurodegenerative disorders and many heart diseases. The proteasome is pivotal to the timely removal of abnormal proteins but its functional capacity often becomes inadequate in the disease conditions; consequently, proteasome functional insufficiency in return exacerbates IPTS. Recent research in proteasome biology reveals that the proteasome can be activated by endogenous protein kinases, making it possible to pharmacologically prime the proteasome for treating diseases with IPTS.

Keywords: cAMP-dependent protein kinase; cGMP-dependent protein kinase; desmin-related cardiomyopathy; phosphodiesterases; proteasome; proteotoxicity.

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Figures

Figure 1.
Figure 1.. The composition of the 26S proteasome and an illustration of a 26S proteasome nanodomain.
A, The 26S proteasome contains a cylinder-shaped 20S core particle capped by a 19S regulatory particle at one or both ends. The 20S is an axial stack of four rings: two outer α-rings and two inner β-rings. Each ring is formed by 7 protein subunits: α1 through α7 for the α ring and β1 through β7 for the β ring. The proteasomal peptidase activities reside in β1, β2, and β5 subunits while the α ring gates substrate access to the proteolytic chamber of the 20S. The 19S consists of a lid and a base subcomplex; the lid is formed primarily by the non-ATPase subunits RPNs and the base is composed of six ATPase subunits (RPT1 through RPT6). B, An illustration of a 26S proteasome nanodomain. Main regulators of the cAMP/PKA and the cGMP/PKG signaling modules are highlighted in the pink and the blue zone, respectively. Both cAMP/PKA and cGMP/PKG activate the 26S proteasome. PKA does so via the selective phosphorylation of the Ser14 of RPN6 (p-S14-RPN6), a 19S lid subunit strategically positioned to interact with both the base of the 19S and the α-ring of the 20S. PKG primes the proteasome perhaps through phosphorylating RPT6 and β5subunits.
Figure 2.
Figure 2.. A schema for proposed duo-activation of PKA and PKG to treat cardiac disease with IPTS.
PDE3 inhibition (PDE3i), PDE4 inhibition (PDE4i) as well as activation of the adenylate cyclase (AC) (dark red) are expected to augment cAMP/PKA signaling, which leads to increased Ser14-phosphorylated RPN6/PSMD11 (p-S14-RPN6) and thereby increases proteasome (Psm) activities and perhaps 26S Psm assembly, which in turn facilitates the degradation of misfold proteins and protects proteotoxicity. In parallel, PDE5i, PDE10i or using an activator or stimulator of soluble guanylate cyclase (sGC) (blue) will augment cGMP/PKG signaling, which increases proteasome activities by phosphorylating Psm subunit(s) that remains to be identified and promotes the degradation of misfolded proteins. Stimulating cAMP/PKA promotes cardiac growth (hypertrophy) and increases heart rate (HR), which raises cardiac oxygen consumption and represents undesirable effects. Augmentation of cGMP/PKG signaling, on the other hand, suppresses hypertrophy and decreases HR, which in some cases may not be beneficial either. Hence, duo-activation of PKA and PKG is expected to cancel out some of their undesirable non-Psm effects while complementarily prime the Psm. The duo-activation may be achievable by PDE1 inhibition (PDE1i) or PDE10 inhibition (PDE10i) but PDE1 and PDE10i do not necessarily equally raise cAMP and cGMP in a given cell type; consequently, a proper combination of a method from the PKA activation side and one from the PKG activation side would likely better serve the purpose. The dot lines denote conceivable alternative pathways that currently have no clear support.
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