Apoptosis regulation by autophagy gene 5

Abstract

Autophagy is a cellular process, in which cellular proteins and cytoplasmic organelles are degraded. It reflects the response of a cell to stress or starvation with the primary goal of cell survival. On the other hand, if the autophagic activity is too high, cell death happens, suggesting that this process requires a tight control. Autophagic cell death has often been observed under conditions, in which apoptosis is blocked. Recent studies suggest that autophagy may promote apoptosis and that Bcl-2 cannot block only apoptosis, but also autophagy and autophagic cell death. Here, we discuss recent findings regarding the interrelations between autophagy and apoptosis. In particular, we would like to draw the attention of the readers to Atg5, which exhibits, like Bcl-2, a dual function by modulating both autophagy and apoptosis.

Introduction

Apoptosis is the most common form of physiologic cell death in multicellular organisms. It is morphologically characterized by cell shrinkage, chromatin condensation, and membrane blebbing [1]. The main biochemical features are activation of intracellular proteases (in particular caspases) and internucleosomal DNA fragmentation. In most cases, cells undergo apoptosis in the absence of inflammation. Apoptosis can be mediated by death receptors or cell stress (e.g., anticancer drugs, ultraviolet light, gamma-irradiation, growth factor deprivation). Mitochondria play a key role in pro-apoptotic pathways that release pro-apoptotic proteins (e.g., cytochrome c, Smac) under the control of proteins of the Bcl-2 family [2]. The released mitochondrial pro-apoptotic proteins lead to increased caspase activation [3].

Autophagy is a process in a cell that serves to degrade long-lived proteins and to recycle cellular components to ensure survival during starvation. It is further characterized by extensive intracellular membrane remodeling, engulfing portions of the cytoplasm in large double-membrane vesicles, called autophagosomes. Autophagosomes subsequently fuse with lysosomes, leading to degradation of their content [4]. Autophagy is controlled by autophagy genes (Atgs). Besides its central role during starvation [5], [6], autophagy has been shown to play a role in tumor suppression [7], [8], pathogen killing [9], antigen presentation [10], and the regulation of the lifespan of the whole organism [11].

The involvement of autophagy in programmed cell death has been controversial. Autophagy is considered to be a survival mechanism. However, changes in autophagic activity can result in cell death (Fig. 1). Some, but not all, cancers have reduced autophagic activity [7], [8]. This may explain, why anticancer drugs, which increase autophagic activity, can induce both efficacy and drug resistance [12]. Moreover, since many human cancers exhibit mutations in pro-autophagy genes, sufficient autophagic activity might be important for tumor suppression [13]. On the other hand, autophagy enhances the survival of tumor cells under conditions of nutrient shortage and/or metabolic stress [14]. Taken together, the molecular mechanisms regulating cell survival and cell death within the process of autophagy are currently not understood.