The functions of Atg8-family proteins in autophagy and cancer: linked or unrelated?

Abstract

The Atg8-family proteins are subdivided into two subfamilies: the GABARAP and LC3 subfamilies. These proteins, which are major players of the autophagy pathway, present a conserved glycine in their C-terminus necessary for their association to the autophagosome membrane. This family of proteins present multiple roles from autophagy induction to autophagosome-lysosome fusion and have been described to play a role during cancer progression. Indeed, GABARAPs are described to be downregulated in cancers, and high expression has been linked to a good prognosis. Regarding LC3 s, their expression does not correlate to a particular tumor type or stage. The involvement of Atg8-family proteins during cancer, therefore, remains unclear, and it appears that their anti-tumor role may be associated with their implication in selective protein degradation by autophagy but might also be independent, in some cases, of their conjugation to autophagosomes. In this review, we will then focus on the involvement of GABARAP and LC3 subfamilies during autophagy and cancer and highlight the similarities but also the differences of action of each subfamily member.Abbreviations: AIM: Atg8-interacting motif; AMPK: adenosine monophosphate-associated protein kinase; ATG: autophagy-related; BECN1: beclin 1; BIRC6/BRUCE: baculoviral IAP repeat containing 6; BNIP3L/NIX: BCL2 interacting protein 3 like; GABARAP: GABA type A receptor-associated protein; GABARAPL1/2: GABA type A receptor associated protein like 1/2; GABRA/GABA_A: gamma-aminobutyric acid type A receptor subunit; LAP: LC3-associated phagocytosis; LMNB1: lamin B1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PI4K2A/PI4KIIα: phosphatidylinositol 4-kinase type 2 alpha; PLEKHM1: plecktrin homology and RUN domain containing M1; PtdIns3K-C1: class III phosphatidylinositol 3-kinase complex 1; SQSTM1: sequestosome 1; ULK1: unc51-like autophagy activating kinase 1.

Keywords: Atg8; GABARAP; GABARAPL1; GABARAPL2; LC3; autophagy; cancer.

Figure 1.

Role of Atg8-family proteins during the autophagy pathway. Top: Molecular mechanism of autophagy. ① Autophagy is induced by cellular stresses (hypoxia, amino acid [AA] starvation …), AMPK activation, and MTOR inactivation leading to ULK1 activation and recruitment to the phagophore. ② LC3s and GABARAPs proteins, previously cleaved by ATG4 proteases, are then conjugated to phosphatidylethanolamine (PE) or phosphatidylserine (PS) to give the membrane-bound forms of these proteins, LC3s-II and GABARAPs-II. ③ These proteins then play a major role in phagophore elongation and the GABARAPs during closure. ④ The closed autophagosome then re-localizes to the perinuclear space thanks to its interaction with the microtubules ⑤, where it fuses with a lysosome to induce the degradation of its content. ① GABARAPL1 is implicated in MTOR inactivation and AMPK activation, leading to ULK1 activation. ② GABARAP has also been described to be involved in ULK1 activation, while GABARAPL1, like GABARAP, is more efficient in the recruitment of ULK1 to the autophagosome than the LC3s proteins. ③ The PtdIns3K-C1 complex, composed of PIK3C3, ATG14, and other proteins, is recruited to the phagophore through its interaction with Atg8-family proteins, but interacts preferentially with GABARAP and GABARAPL1, inducing the phosphorylation of ATG14 by ULK1 and then the activation of this complex. ER, endoplasmic reticulum. Bottom: Involvement of GABARAPs (GBPs) and LC3B proteins during the early and late stages of autophagy in mammals. ✓, high implication; ✓, low implication; ×, not described to be implicated in mammals

Figure 2.

Proposed model describing the role of Atg8-family proteins during the late stages of autophagy. Atg8-family proteins induce ① autophagosome intracellular re-localization through their interaction with FYCO1 or MAPK8IP1 (A), which binds microtubule molecular motors. Atg8-family proteins can also directly bind microtubules (B) or molecular motors, such as dynein (C), to redistribute autophagosomes in cells. Atg8-family proteins also induce ② autophagosome-lysosome fusion through their interaction with PLEKHM1 or BIRC6 (a), two lysosomal proteins, or through PI4K2A recruitment (b) from the Golgi apparatus to facilitate fusion events. AP, autophagosome; MTOC, microtubule-organizing center

Figure 3.

Schematic representation of Atg8-family protein (Atg8) involvement during selective autophagy and recruitment. ① Atg8-family proteins are docked at the phagophore membrane by their lipidation and act as recruiters of proteins that will not be degraded through autophagy. These proteins are brought to the autophagosome external membrane (convex side) to allow an efficient autophagosome formation and include proteins such as GABARAP, ULK1, and PtdIns3K-C1 complexes during the early stage of autophagy or with the lysosomal proteins BIRC6, PLEKHM1, ATG2, and PI4K2A during autophagosome-lysosome fusion. ② During selective autophagy, Atg8-family proteins interact with the cargo receptor (CR) through the W and L hydrophobic pockets of Atg8-family proteins with the AIM of the CR. The CR interacts with the ubiquitinated cargo (e.g., mitochondria, protein aggregates) to facilitate degradation