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Review
, 40 (7), 441-449

Crosstalk and Interplay Between the Ubiquitin-Proteasome System and Autophagy

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Review

Crosstalk and Interplay Between the Ubiquitin-Proteasome System and Autophagy

Chang Hoon Ji et al. Mol Cells.

Abstract

Proteolysis in eukaryotic cells is mainly mediated by the ubiquitin (Ub)-proteasome system (UPS) and the autophagylysosome system (hereafter autophagy). The UPS is a selective proteolytic system in which substrates are recognized and tagged with ubiquitin for processive degradation by the proteasome. Autophagy is a bulk degradative system that uses lysosomal hydrolases to degrade proteins as well as various other cellular constituents. Since the inception of their discoveries, the UPS and autophagy were thought to be independent of each other in components, action mechanisms, and substrate selectivity. Recent studies suggest that cells operate a single proteolytic network comprising of the UPS and autophagy that share notable similarity in many aspects and functionally cooperate with each other to maintain proteostasis. In this review, we discuss the mechanisms underlying the crosstalk and interplay between the UPS and autophagy, with an emphasis on substrate selectivity and compensatory regulation under cellular stresses.

Keywords: N-end rule pathway; N-terminal arginylation; degradation signal (degron); macroautophagy; protein quality control; proteolysis; ubiquitin code.

Figures

Fig. 1
Fig. 1. The crosstalk from the UPS to autophagy
The inhibition of the UPS results in the compensatory activation of autophagy. Proteasomal inhibition in the ER impairs ERAD and causes ER stress and the UPR. PERK and IRE1α subsequently activate downstream pathways toward autophagy. The PERK- eIF2α circuit accelerates the synthesis of the transcription factors ATF4 and CHOP, leading to the expression of ATG genes. Activated IRE1 recruits TRAF2, leading to the phosphorylation of JNK and the expression of autophagic core genes. In parallel, ATF6 is cleaved in the Golgi and translocates to the nucleus, where it induces the expression of DAPK1 and its phosphorylation of beclin-1 for autophagosome biogenesis. In addition, accumulated p53 upon proteasomal inhibition translocates to the nucleus and acts as a transcription factor for autophagy housekeeping genes such as DRAM. Alternatively, increased p53 levels may activate AMPK-dependent autophagy by inhibiting the mTOR pathway.
Fig. 2
Fig. 2. The crosstalk from autophagy to the UPS
Autophagic inhibition can impair proteasomal flux, leading to the accumulation of ubiquitinated substrates and their aggregates. In this model, autophagic inhibition causes the accumulation of misfolded proteins and aggregates associated with p62 aggregates, which, in turn, sequester ubiquitinated substrates from the UPS machinery and the regulators of the UPS, such as p97/VCP. In addition, autophagy inhibition can impair the autophagic degradation of the proteasome, leading to the accumulation of aging or damaged proteasomes at the expense of healthy and normal proteasomes.
Fig. 3
Fig. 3. Modulation of macroautophagy by the N-terminal arginylation
The accumulation of misfolded proteins and their aggregates stimulates the cytosolic relocalization and N-terminal arginylation of ER-residing chaperones such as BiP, calreticulin, and protein disulfide isomerase. Cytosolic R-BiP is associated with cargoes and bind the ZZ domain of p62, facilitating p62 self-polymerization and interaction with LC3. In addition, the ligand-bound p62 induces autophagosome biogenesis. Through this dual regulation, cells can efficiently remove misfolded proteins in a real time basis.

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