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Review
, 293 (15), 5404-5413

Ubiquitin Signaling and Autophagy

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Review

Ubiquitin Signaling and Autophagy

Paolo Grumati et al. J Biol Chem.

Abstract

Ubiquitination is a widespread post-translational modification that controls multiple steps in autophagy, a major lysosome-mediated intracellular degradation pathway. A variety of ubiquitin chains are attached as selective labels on protein aggregates and dysfunctional organelles, thus promoting their autophagy-dependent degradation. Moreover, ubiquitin modification of autophagy regulatory components is essential to positively or negatively regulate autophagy flux in both non-selective and selective pathways. We review the current findings that elucidate the components, timing, and kinetics of the multivalent role of ubiquitin signals in control of amplitude and selectivity of autophagy pathways as well as their impact on the development of human diseases.

Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article

Figures

Figure 1.
Figure 1.
Involvement of ubiquitin signaling in autophagy initiation and termination. Upon a stress stimulus, autophagy machinery is immediately activated. A, two conserved ubiquitin-like systems, involving ATG4–ATG3–ATG7 and ATG7-ATG5–ATG12–ATG16L, are responsible for the mATG8s processing. B, ULK1 and PI3K complexes are activated via Lys-63 polyubiquitin chains labeling ULK1 and BECLIN 1 proteins. Proteasome elimination of cytosolic phospho-TFEB promotes lysosome biogenesis and autophagy gene transcription. C, once the stress situation is resolved, autophagy is shut down to avoid excessive cellular catabolism. Degradative-ubiquitin signals determine proteasome elimination of the autophagy regulative proteins.
Figure 2.
Figure 2.
Autophagy receptors bind to Lys-63 polyubiquitin chains and recruit phagophores to the cargo. A, in aggrephagy, multiple E3 ligases are involved in the protein aggregate ubiquitination. p62 and NBR1 receptors are recruited via Lys-63 chains. SUMO, FAT10, and ISG15 are other ubiquitin-like proteins, which label the protein aggregate surface. ISG15 interacts with p62, whereas BAG3 binds simultaneously Lys-48 Ub chains and p62 redirecting Lys-48 substrates to lysosomes. B, during mitophagy, PARKIN translocates to the mitochondria, where it mediates the ubiquitination of a plethora of mitochondrial proteins. OMM proteins, which are involved in the mitochondrial fusion process and anchorage to the cytoskeleton, are degraded via proteasome. Isolated single organelles are then recognized by autophagy receptors via Lys-63 polyubiquitin chains. C, damaged lysosomes are eliminated via autophagy, too. To recruit LC3 on the lysosome surface, Lys-48 polyubiquitin chains must be removed by the ELDR complex. Lys-63 chains are unaffected by ELDR, so they promote autophagy receptor recruitment. The E3 ligases involved in lysosome ubiquitination are so far unknown. D, upon infection, the Salmonella surface is tagged by several E3 ligases as a defense mechanism. LRSAM1 and ARIH add, respectively, Lys-6–Lys-27 and Lys-48 poly-Ub chains. Linear Ub chains are formed and regulated by the HOIP1 and OTULIN (LUBAC complex), whereas the E3 ligase responsible for Lys-63 chains is unknown. The autophagy machinery is recruited by Lys-63 and linear chains.

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