Immunologic manifestations of autophagy

7 5 jci.org Volume 125 Number 1 January 2015 Introduction The term autophagy in its broadest sense refers to a set of diverse processes that deliver cytoplasmic constituents to lysosomes for degradation. In this Review, we focus only on the sensu stricto autophagy as a well-delineated pathway controlled by autophagyrelated gene–encoded (ATG-encoded) factors (1). Since general roles of autophagy in immunity have been extensively covered recently (2, 3), here we primarily give a summary with an update and extend this to a focus on one of the early paradigms of autophagy in immune defense — control of Mycobacterium tuberculosis (4). Our understanding of this model system has continued to evolve since the initial reports that autophagy can eliminate intracellular bacteria (4, 5) and helps to illustrate a number of general immunologic manifestations of autophagy. A cardinal structural and functional feature of autophagy is the formation of organelles called autophagosomes. The formation of autophagosomes is under the control of the ATG factors Unc51 like autophagy activating kinase 1/2 (ULK1/2; Atg1 in yeast), beclin 1 (Atg6 in yeast), and mammalian paralogs of yeast Atg8 (light chain 3A [LC3A], LC3B, LC3C, GABARAP, GABARAPL1, and GABARAPL2) (ref. 1 and Figure 1A). A cascade of events controlled by these and additional ATG factors leads to the formation of a phagophore from several membrane sources including ER (6) and the endosomal system (7). Recently, additional contributions of phospholipid precursors and signals from lipid droplets have been recognized (8). The phagophore elongates, captures cytoplasmic targets earmarked for autophagic degradation, and following closure, delivers them to lysosomes (1). Evolutionarily, autophagy may be the earliest form of eukaryotic innate defense against invading microorganisms. Competition for intracellular nutrients might have been one of the most primordial danger signals available to the eukaryotic cell to detect microbial invasion and eliminate microbes through autophagy. This is manifested in present-day relationships. For example, metabolic signaling downstream of starvation is associated with antimicrobial autophagy in response to bacterial invasion (9). Starvation can induce autophagy to kill virulent M. tuberculosis in macrophages (4). Thus, the classical starvation signals for autophagy should also be considered as signals for immune defenses. The nutritional signals leading up to autophagy activation are transduced by mTOR and AMPK. mTOR inhibits ULK1 by phosphorylating residues at inactivating sites (e.g., Ser757), whereas AMPK stimulates ULK1 by phosphorylating ULK1 at activating residues (e.g., Ser317 and Ser777) (10, 11). Activated ULK1 phosphorylates beclin 1 at Ser15 (12). Additionally, AMPK directly phosphorylates beclin 1 at Ser91/Ser94 and helps activate it (13). Furthermore, K63 ubiquitination events lead to stabilization of the autophagy regulatory complexes (14, 15). These events set off a complex cascade of membrane trafficking transactions governing initiation of autophagy, elongation of phagophores, and maturation of autophagic organelles into autolysosomes.