Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 40 (12), 897-905

Emerging Paradigm of Crosstalk Between Autophagy and the Ubiquitin-Proteasome System


Emerging Paradigm of Crosstalk Between Autophagy and the Ubiquitin-Proteasome System

Taewook Nam et al. Mol Cells.


Cellular protein homeostasis is maintained by two major degradation pathways, namely the ubiquitin-proteasome system (UPS) and autophagy. Until recently, the UPS and autophagy were considered to be largely independent systems targeting proteins for degradation in the proteasome and lysosome, respectively. However, the identification of crucial roles of molecular players such as ubiquitin and p62 in both of these pathways as well as the observation that blocking the UPS affects autophagy flux and vice versa has generated interest in studying crosstalk between these pathways. Here, we critically review the current understanding of how the UPS and autophagy execute coordinated protein degradation at the molecular level, and shed light on our recent findings indicating an important role of an autophagy-associated transmembrane protein EI24 as a bridging molecule between the UPS and autophagy that functions by regulating the degradation of several E3 ligases with Really Interesting New Gene (RING)-domains.

Keywords: EI24; RING-domain; autophagy; crosstalk; ubiquitin proteasome system.


Fig. 1
Fig. 1. EI24 as a central molecule facilitating communication between autophagy and the UPS
The UPS comprises ATP-dependent concerted action of the E1, E2, and E3 enzyme cascade that results in the ubiquitination of target proteins and degradation in the proteasome. RING-domain E3 ligases are the central molecules of the UPS machinery and function by catalyzing the transfer of ubiquitin chains to target proteins. Recently, we unraveled the novel connection of the UPS to the autophagy pathway through the ability of autophagy-inducing protein EI24 to bind to and degrade RING-domain E3 ligases through autophagy machinery. EI24 acts as a connecting link to facilitate the recruitment of RING-domain E3 ligases to the autophagosome and their ultimate degradation in the autophagolysosome.

Similar articles

See all similar articles

Cited by 17 articles

See all "Cited by" articles


    1. Araki K., Nagata K. Protein folding and quality control in the ER. Cold Spring Harb Perspect Biol. 2011;3:a007526. - PMC - PubMed
    1. Ardley H.C., Robinson P.A. E3 ubiquitin ligases. Essays Biochem. 2005;41:15–30. - PubMed
    1. B’Chir W., Maurin A.C., Carraro V., Averous J., Jousse C., Muranishi Y., Parry L., Stepien G., Fafournoux P., Bruhat A. The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013;41:7683–7699. - PMC - PubMed
    1. Boucas J., Fritz C., Schmitt A., Riabinska A., Thelen L., Peifer M., Leeser U., Nuernberg P., Altmueller J., Gaestel M., et al. Label-free protein-RNA interactome znalysis identifies Khsrp signaling downstream of the p38/Mk2 kinase complex as a critical modulator of cell cycle progression. PLoS One. 2015;10:e0125745. - PMC - PubMed
    1. Budenholzer L., Cheng C.L., Li Y., Hochstrasser M. Proteasome structure and Assembly. J Mol Biol. 2017;429:3500–3524. - PMC - PubMed

MeSH terms