Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks

Abstract

Living cells are adaptive self-sustaining systems. They strictly depend on the sufficient supply of oxygen, energy, and nutrients from the outside in order to sustain their internal organization. However, as autonomous entities they are able to monitor and appropriately adapt to any critical fluctuation in their environment. In the case of insufficient external nutrient supply or augmented energy demands, cells start to extensively digest their own interior. This process, known as macroautophagy, comprises the transport of cytosolic portions and entire organelles to the lysosomal compartment via specific double-membrane vesicles, called autophagosomes. Although extensively upregulated under nutrient restriction, a low level of basal autophagy is likewise crucial in order to sustain the cellular homeostasis. On the other hand, cells have to avoid excessive and enduring self-digestion. The delicate balance between external energy and nutrient supply and internal production and consumption is a demanding task. The complex protein network that senses and precisely reacts to environmental changes is thus mainly regulated by rapid and reversible posttranslational modifications such as phosphorylation. This review focuses on the serine/threonine protein kinases AMP-activated protein kinase, mammalian target of rapamycin (mTOR), and unc-51-like kinase 1/2 (Ulk1/2), three interconnected major junctions within the autophagy regulating signaling network. AMPK: THE ENERGY-SENSING KINASEA MP-activated protein kinase (AMPK) was initially identified as a serine/threonine kinase that negatively regulates several key enzymes of the lipid anabolism (30). Meanwhile, AMPK is regarded as the major energy-sensing kinase that activates a whole variety of catabolic processes in multicellular organisms such as glucose uptake and metabolism, while simultaneously inhibiting several anabolic pathways, such as lipid, protein, and carbohydrate biosynthesis (reviewed in reference 30).AMPK is a heterotrimeric protein complex that is precisely regulated in different ways. First, the phosphorylation of a conserved threonine residue (T172) in the activation loop of the catalytic ␣-subunit by upstream kinases is a prerequisite for the activity of AMPK. Several AMPK-phosphorylating kinases have been identified thus far. In addition to the ubiquitously expressed and constitutively active kinase LKB1 (31, 109), Ca 2ϩ -activated Ca 2ϩ /calmodulin-dependent kinase kinase ␤ (CaMKK␤) (32,43,108) and transforming growth factor ␤-activated kinase-1 (TAK1) (80) are both known as activators of AMPK. Second, AMPK activity can further be modulated by allosteric binding to the regulatory ␤-and ␥-subunit. Since the ratio of AMP to ATP represents the most accurate way to precisely measure the intracellular energy level, both AMP and ATP are able to oppositely regulate the activity of AMPK. While AMP binding to the ␥-subunit allosterically enhances AMPK kinase activity and prevents the dephosphorylation of T172, ATP is known to counteract the activating properties...

β‐Guanidinopropionic acid extends the lifespan of Drosophila melanogaster via an AMP‐activated protein kinase‐dependent increase in autophagy

“…Recent studies have addressed a new mechanism for the control of mammalian autophagy by AMPK that AMPK regulates autophagy through direct phosphorylation of ULK1 (Alers et al ., 2012). To determine the role of AMPK activation in the effect of β‐GPA on lifespan in Drosophila , compound C (an AMPK inhibitor) and RNA interference were employed.…”

“…Our study showed that the elevated levels of autophagy and lifespan extension induced by β‐GPA were abolished by Atg1‐RNAi. ULK1/Atg1‐dependent autophagy is regulated by the mammalian target of rapamycin complex 1 (mTORC1) and AMPK (Alers et al ., 2012). Notably, the activity of ULK1/Atg1 kinase increases in an AMPK‐dependent manner following glucose deprivation (Alers et al ., 2012).…”

“…ULK1/Atg1‐dependent autophagy is regulated by the mammalian target of rapamycin complex 1 (mTORC1) and AMPK (Alers et al ., 2012). Notably, the activity of ULK1/Atg1 kinase increases in an AMPK‐dependent manner following glucose deprivation (Alers et al ., 2012). Recent studies demonstrate that AMPK directly phosphorylates ULK1/Atg1 on several sites, and this phosphorylation is required for ULK1/Atg1 activation after glucose deprivation (Alers et al ., 2012).…”

“…Notably, the activity of ULK1/Atg1 kinase increases in an AMPK‐dependent manner following glucose deprivation (Alers et al ., 2012). Recent studies demonstrate that AMPK directly phosphorylates ULK1/Atg1 on several sites, and this phosphorylation is required for ULK1/Atg1 activation after glucose deprivation (Alers et al ., 2012). On the contrary, when nutrients are plentiful, the mTORC1 complex phosphorylates ULK1/Atg1, preventing the association and activation of ULK1/Atg1 by AMPK (Alers et al ., 2012).…”

“…As a conserved process participating bioenergetic management by degrading and recycling cellular constituents, autophagy has been recently proposed as a downstream target of AMPK (Wong et al ., 2009). Experiments in mammals have demonstrated that AMPK controls autophagy through mammalian target of rapamycin (mTOR) and Atg1/ULK1 signalings, which augments the quality of cellular housekeeping (Alers et al ., 2012). Previous studies indicate that the activation of AMPK is able to induce autophagy and subsequently confer to the protective effects against ischemic injury in the heart (Matsui et al ., 2007), kidney (Wang et al ., 2013), liver (Zaouali et al ., 2013), and muscular tissues (Pauly et al ., 2012).…”