14-3-3 proteins: an important regulator of autophagy in diseases

Abstract

Autophagy is a cell digestion process that determines cell fate by promoting cell survival or inducing cell death in a cell context-dependent manner. Several classical signaling pathways, such as phosphoinositide-3-kinase and mammalian target of rapamycin, tightly regulate autophagy. 14-3-3 proteins regulate various signaling pathways by phosphorylation-dependent binding with partner proteins. 14-3-3 proteins also regulate autophagy by binding with autophagy-related proteins such as Beclin-1 and hVPS34. This review summarizes the role of 14-3-3 proteins in the control of autophagy in cancer, neurodegenerative diseases and other pathological conditions.

Keywords: 14-3-3 proteins; autophagy; cancer; neurodegenerative diseases.

Figure 1

Model of regulation of autophagy process. The ULK1-Atg13-FIP200 complex promotes the recruitment of PI3K/Vps34 complex to phagophore membranes. The Atg12-Atg5-Atg16 complex and Atg8/LC3 are involved inthe elongation and expansion steps of autophagosome formation. MAPK and PI3K inhibit autophagy by activating the mTOR complex; however, P53 has the opposite effect. AMPK activates autophagy by upregulating the ULK1 complex.

Figure 2

Model of the biological process of 14-3-3 proteins regulation. The 14-3-3 family contains seven isoforms (β, ε, η, γ, τ, σ, and ζ), all of which bind to target proteins and alter the modification, intercellular localization, and activity of target proteins by interacting with specific phosphothreonine and phosphoserine motifs, and then regulating the biological processes.

Figure 3

Model of 14-3-3 regulation of autophagy in cancers. 14-3-3 proteins inhibit or promote autophagy by binding with autophagy-related proteins to promote cancer cell survival or apoptosis. AKT inhibits autophagy by phosphorylating Beclin-1 at the S295 site and enhancing the formation of the Beclin-1/14-3-3/vimentin complex to promote tumorigenesis. AKT1S1 binds with 14-3-3 to promote cancer cell growth by inhibiting autophagy. PI3K inhibitors promote the dissociation of FOXO3a from 14-3-3ζ to induce autophagy. The GS3K inhibitor induces TFEB dephosphorylation and its dissociation from 14-3-3 and subsequently induces TFEB activation and nuclear translocation to activate autophagy. MK2 induces TSC2 phosphorylation and formation of TSC2/14-3-3 complex to promote autophagy. By contrast, 14-3-3 inhibits autophagy by binding with hVPS34 to induce cell apoptosis.