Amino acid deprivation promotes intestinal homeostasis through autophagy

Macroautophagy (here below referred to as autophagy) is a fundamental gatekeeper of intracellular homeostasis. On the one hand, autophagy operates at baseline levels to dispose of damaged organelles and other potentially cytotoxic byproducts of normal cellular functions, hence preserving metabolic and redox fitness in physiological conditions [1]. On the other hand, the autophagic machinery is functionally connected to sensors that continuously monitor the intracellular and extracellular milieu for chemical, physical, biological, infectious and metabolic threats. Thus, cells continuously adapt autophagic flux (i.e., the actual degradation of autophagic substrates by lysosomes) to cope with potentially dangerous fluctuations of homeostasis [2]. Corroborating the central cytoprotective function of autophagy, pharmacological agents or genetic interventions that inhibit one fundamental component of the autophagic machinery most often precipitate the demise of cells responding to stress [3]. Accumulating data indicate that autophagy does not only occupy a key position in cell-intrinsic responses to stress, but also stands at the hub of several cell-extrinsic mechanisms of preservation of organismal homeostasis [4]. Ravindran et al. recently demonstrated that the amino acid-responsive sensor eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4; best known as general control nonderepressible 2, GCN2) dampens intestinal inflammation via a cell-extrinsic mechanism that involves autophagy [5]. These findings lend further support to the conjecture that the capacity of autophagy to preserve homeostasis trespasses the virtual boundary represented by the plasma membrane.