786 Biochemical Society Transactions (2008) Volume 36, part 5 Life, death and burial: multifaceted impact of autophagy Lorenzo Galluzzi, Eugenia Morselli, Jos ´ e Miguel Vicencio, Oliver Kepp, Nicholas Joza, Nicolas Tajeddine and Guido Kroemer 1 Inserm U848, Institut Gustave Roussy, Universit ´ e Paris-Sud 11, PR1, 39 rue Camille Desmoulins, 94805 Villejuif, France Abstract Macroautophagy, often referred to as autophagy, designates the process by which portions of the cytoplasm, intracellular organelles and long-lived proteins are engulfed in double-membraned vacuoles (autophagosomes) and sent for lysosomal degradation. Basal levels of autophagy contribute to the maintenance of intracellular homoeostasis by ensuring the turnover of supernumerary, aged and/or damaged components. Under conditions of starvation, the autophagic pathway operates to supply cells with metabolic substrates, and hence represents an important pro-survival mechanism. Moreover, autophagy is required for normal development and for the protective response to intracellular pathogens. Conversely, uncontrolled autophagy is associated with a particular type of cell death (termed autophagic, or type II) that is characterized by the massive accumulation of autophagosomes. Regulators of apoptosis (e.g. Bcl-2 family members) also modulate autophagy, suggesting an intimate cross-talk between these two degradative pathways. It is still unclear whether autophagic vacuolization has a causative role in cell death or whether it represents the ultimate attempt of cells to cope with lethal stress. For a multicellular organism, autophagic cell death might well represent a pro-survival mechanism, by providing metabolic supplies during whole-body nutrient deprivation. Alternatively, type II cell death might contribute to the disposal of cell corpses when heterophagy is deficient. Here, we briefly review the roles of autophagy in cell death and its avoidance. Introduction The term autophagy (i.e. self-eating, from the Greek words auto = self and phagein = to eat) comprises a number of multiple intracellular processes, including CMA (chaperone- mediated autophagy), micro- and macro-autophagy, which converge on a common degradation phase mediated by lysosomes [1,2]. During CMA, cytosolic proteins containing a specific pentapeptide domain (consensus sequence = KFERQ) are unfolded and directly translocated across the lysosomal membrane [3]. On the contrary, a sequestering membrane is implicated in both micro- and macro-autophagy, yet only in the latter the engulfing apparatus is accounted for by an organelle distinct from lysosomes, known as AV (autophagic vacuole) or autophagosome [4]. For the sake of brevity, macroautophagy will be referred to as autophagy here. During autophagy, portions of the cytoplasm (including organelles) are sequestered by a membrane of still unidenti- fied origin (the so-called phagophore or isolation membrane), which progressively enwraps the components targeted for de- gradation and eventually forms a double-membraned AV. At Key words: apoptosis, atg gene, Bcl-2, Beclin 1, macroautophagy, mitochondrion. Abbreviations used: AV, autophagic vacuole; AV-I, early AV; AV-II, late AV; atg gene, a ut ophag y- related gene; Bec-1, Beclin 1; CMA, chaperone-mediated autophagy; DIF, differentiation-inducing factor; DISC, death-inducing signalling complex; ER, endoplasmic reticulum; FADD, Fas-associated death domain; IFN-γ , interferon-γ ; IL-3, interleukin-3; 3-MA, 3-methyladenine; MEF, mouse embryonic fibroblast; RNAi, RNA interference; siRNA, small interfering RNA; TLR, Toll-like receptor. 1 To whom correspondence should be addressed (email kroemer@igr.fr). this stage, AV-Is (early AVs) contain prominently undegraded components. Upon fusion with lysosomes, lysosomal acidic hydrolases enter the AV lumen and degrade its content. These vesicles, known as AV-IIs (late AVs), are delimited by a single membrane and surround an electron-dense content. Finally, the macromolecules generated by autophagy are released into the cytosol and can re-enter metabolic reactions [5]. Autophagy has been implicated in a broad range of patho- physiological conditions (Table 1) [6]. First, it represents a prominent mechanism of cellular adaptation to stress, such as increased temperature, high population density and nutrient deprivation. Under carbon and nitrogen starvation, for in- stance, the activity of the mTOR (mammalian target of rapa- mycin; the major negative regulator of autophagy) is rapidly shut down, and the ensuing up-regulation of the autophagic pathway supplies cells with metabolic substrates to meet their bioenergetic demands [1]. Secondly, autophagy is activated in response to invasion by intracellular pathogens [7] and plays a multifaceted role in innate and adaptive immunity, by promoting the degradation of invading microbes (xeno- phagy), by delivering viral nucleic acids to TLRs (Toll-like receptors), by contributing to the phagocytic pathway, and by feeding antigens to MHC class II compartments [8–10]. Thirdly, autophagy is implicated in several scenarios of stress- induced differentiation and normal development [6]. Thus atg (a ut ophag y-related) genes (which encode proteins required in the various phases of the autophagic pathway [5]) are neces- sary for specific developmental programmes that are activated C  The Authors Journal compilation C  2008 Biochemical Society Biochem. Soc. Trans. (2008) 36, 786–790; doi:10.1042/BST0360786 Biochemical Society Transactions www.biochemsoctrans.org