Autophagy as a modulator of cell death machinery

Abstract

The balance between cell death and survival is a critical parameter in the regulation of cells and the maintenance of homeostasis in vivo. Three major mechanisms for cell death have been identified in mammalian cells: apoptosis (type I), autophagic cell death (type II), and necrosis (type III). These three mechanisms have been suggested to engage in cross talk with each other. Among them, autophagy was originally characterized as a cell survival mechanism for amino acid recycling during starvation. Whether autophagy functions primarily in cell survival or cell death is a critical question yet to be answered. Here, we present a comprehensive review of the cell death-related events that take place during autophagy and their underlying mechanisms in cancer and autoimmune disease development.

Fig. 1. Cross talk regulation between autophagy and apoptosis.

Autophagy may contribute to enhanced cell death induced by apoptosis, depending on the relative potency of the cell death-inducing stimuli. It is also possible that apoptosis, autophagy, and necrosis, individually or conjointly, act to induce cell death^,,. This complex cross talk underlies the pathogenesis and manifestation of cancer likely through alteration of metabolic status via autophagy^,,. Although autophagy acts as a cytoprotective effect under starvation and/or stress conditions, it is now thought that autophagy also regulates metabolic conditions, which could differentially contribute to the various human diseases such as cancer and autoimmune diseases.

Fig. 2. Lysosomal Akt–Phafin2–VRK2 complex as a functional modulator of autophagy.

Regulatory roles of Akt at the lysosome in the course of autophagy are suggested by Beclin-1 (Atg6), transcription factor EB (TFEB), and Unc-51 like autophagy activating kinase 1 (ULK1) functioning as direct substrates^,,. Recent investigations revealed that target molecules of Akt, such as the tuberous sclerosis complex (TSC), Beclin-1 (ATG6), ULK1, and BAD, are present in the lysosomes^,–. Lysosomes are intracellular organelles that participate in intracellular protein degradation through activating hydrolytic enzymes in the process of autophagy for amino acid recycling^–. Autophagy, a cell survival mechanism during starvation conditions, participates in the regulation of cell death/survival machinery^–. Searching for the binding partner of Akt at the lysosome using yeast two-hybrid screening and time-of-flight/mass spectrometry analyses, we identified the formation of a Akt–Phafin2–VRK2 protein complexes at the lysosome in a phosphatidylinositol 3-phosphate (PtdIns(3)P)-dependent manner^,. A functional study demonstrated the regulatory roles of the Phafin2–VRK2–Akt protein complex at the lysosome in the course of autophagy induction. These findings support the notion that the intersection between autophagic cell death and apoptosis may be at the mitochondria. The presence of the Akt–Phafin2–VRK2 at the lysosome sheds light on the roles of cell death and survival machinery in mammalian cells that may underlie various human diseases including cancer and autoimmune diseases.

Fig. 3. The lysosome and lysosomal membrane permeability are central to the balance of autophagy and apoptosis.

(1) LAMP1, LAMP2, and HSP70 protect lysosomal membrane integrity from lysosomal membrane permeability (LMP) stimuli. (2) Lack of these protein, or increased LMP stimuli such as reactive oxide species (ROS), c-ABL dysfunction, bacteria or virus infection, TNF-α, and staurosporine treatment can disrupt lysosomal membrane integrity resulting in LMP. (3) The decrease in matured lysosomes induced by LMP leads to inhibition of autophagy-dependent protein degradation. (4) LMP also initiates relocalization of lysosomal enzyme such as cathepsins into cytoplasm. (5) Released cathepsins activate caspases resulting in apoptosis.

Fig. 4. LC3-associated phagocytosis (LAP) in the clearance of dying cells.

Generally, phagosomes become decorated with LC3 and are then trafficked to the lysosome for degradation (LC3-associated phagocytosis (LAP)). LAP uses a subset of the autophagy machinery distinct from canonical autophagy. As a result, dying cells are rapidly ingested and degraded and do not induce an autoimmune response. If components of the LAP pathway are lacking, dying cells are not degraded and, hence, the nuclear material escapes, which leads to autoimmune responses. Consequently, a lupus-like systemic inflammatory disease develops.

Fig. 5. IL-21-mTOR axis in the regulation of autophagy in Tregs in SLE.

Autophagy is profoundly diminished in Tregs in SLE. IL-21 induces mTOR activation and eliminates autophagy in Tregs. The blockade of mTOR by rapamycin induces autophagy and recovers the function of Tregs.