Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Upon amino acid starvation or mTOR inhibition the activated ULK1 phosphorylates Beclin-1 on S14, thereby, enhancing the activity of the ATG14L-containing VPS34 complexes. The Beclin-1 S14 phosphorylation by ULK is required for full autophagic induction in mammals and this requirement is conserved in C. elegans. Our study reveals a molecular link from ULK1 to activation of the autophagy specific VPS34 complex and autophagy induction.

The TOR kinases are conserved negative regulators of autophagy in response to nutrient conditions, but the signaling mechanisms are poorly understood. Here we describe a complex containing the protein kinase Atg1 and the phosphoprotein Atg13 that functions as a critical component of this regulation in Drosophila. We show that knockout of Atg1 or Atg13 results in a similar, selective defect in autophagy in response to TOR inactivation. Atg1 physically interacts with TOR and Atg13 in vivo, and both Atg1 and Atg13 are phosphorylated in a nutrient-, TOR-and Atg1 kinase-dependent manner. In contrast to yeast, phosphorylation of Atg13 is greatest under autophagic conditions and does not preclude Atg1-Atg13 association. Atg13 stimulates both the autophagic activity of Atg1 and its inhibition of cell growth and TOR signaling, in part by disrupting the normal trafficking of TOR. In contrast to the effects of normal Atg13 levels, increased expression of Atg13 inhibits autophagosome expansion and recruitment of Atg8/LC3, potentially by decreasing the stability of Atg1 and facilitating its inhibitory phosphorylation by TOR. Atg1-Atg13 complexes thus function at multiple levels to mediate and adjust nutrient-dependent autophagic signaling.

Over the past decade, a brand‐new pressure‐ and tactile‐sensing modality, known as iontronic sensing has emerged, utilizing the supercapacitive nature of the electrical double layer (EDL) that occurs at the electrolytic–electronic interface, leading to ultrahigh device sensitivity, high noise immunity, high resolution, high spatial definition, optical transparency, and responses to both static and dynamic stimuli, in addition to thin and flexible device architectures. Together, it offers unique combination of enabling features to tackle the grand challenges in pressure‐ and tactile‐sensing applications, in particular, with recent interest and rapid progress in the development of robotic intelligence, electronic skin, wearable health as well as the internet‐of‐things, from both academic and industrial communities. A historical perspective of the iontronic sensing discovery, an overview of the fundamental working mechanism along with its device architectures, a survey of the unique material aspects and structural designs dedicated, and finally, a discussion of the newly enabled applications, technical challenges, and future outlooks are provided for this promising sensing modality with implementations. The state‐of‐the‐art developments of the iontronic sensing technology in its first decade are summarized, potentially providing a technical roadmap for the next wave of innovations and breakthroughs in this field.

In response to nutrient deficiency, eukaryotic cells activate macroautophagy, a degradative process in which proteins, organelles and cytoplasm are engulfed within unique vesicles called autophagosomes. Fusion of these vesicles with the endolysosomal compartment leads to breakdown of the sequestered material into amino acids and other simple molecules, which can be used as nutrient sources during periods of starvation. This process is driven by a group of autophagy-related (Atg) proteins, and is suppressed by TOR (target of rapamycin) signalling under favourable conditions. Several distinct kinase complexes have been implicated in autophagic signalling downstream of TOR. In yeast, TOR is known to control autophagosome formation in part through a multiprotein complex containing the serine/threonine protein kinase Atg1. Recent work in Drosophila and mammalian systems suggests that this complex and its regulation by TOR are conserved in higher eukaryotes, and that Atg1 has accrued additional functions including feedback regulation of TOR itself. TOR and Atg1 also control the activity of a second kinase complex containing Atg6/Beclin 1, Vps (vacuolar protein sorting) 15 and the class III PI3K (phosphoinositide 3-kinase) Vps34. During autophagy induction, Vps34 activity is mobilized from an early endosomal compartment to nascent autophagic membranes, in a TOR- and Atg1-responsive manner. Finally, the well-known TOR substrate S6K (p70 ribosomal protein S6 kinase) has been shown to play a positive role in autophagy, which may serve to limit levels of autophagy under conditions of continuously low TOR activity. Further insight into these TOR-dependent control mechanisms may support development of autophagy-based therapies for a number of pathological conditions.

Paper has been utilized as an ideal platform for chemical, biological, and mechanical sensing for its fibrous structures and properties in addition to its low cost. However, current studies on pressure-sensitive papers have not fully utilized the unique advantages of papers, such as printability, cuttability, and foldability. Moreover, the existing resistive, capacitive, and triboelectric sensing modalities have long-standing challenges in sensitivity, noiseproofing, response time, linearity, etc. Here, a novel flexible iontronic sensing mechanism, referred to as iontronic sensing paper (ISP), is introduced to the classic paper substrates by incorporating both ionic and conductive patterns into an all-in-one flexible sensing platform. The ISP can then be structured into 2D or 3D tactile-sensitive origamis only by the paper-specific manipulations of printing, cutting, folding, and gluing. Notably, the ISP device possesses a device sensitivity of 10 nF kPa −1 cm −2 , which is thousands of times higher than that of the commercial counterpart, a resolution of 6.25 Pa, a single-millisecond response time, and a high linearity (R 2 > 0.996). Benefiting from the unique properties of the fibrous paper structures and its remarkable performances, the ISP devices hold enormous potential for the emerging human-machine interfaces, including smart packaging, health wearables, and pressure-sensitive paper matrix.

Autophagy is a highly conserved degradative process that removes damaged or unnecessary proteins and organelles, and recycles cytoplasmic contents during starvation. Autophagy is essential in physiological processes such as embryonic development but how autophagy is regulated by canonical developmental pathways is unclear. Here we show that the Hedgehog signalling pathway inhibits autophagosome synthesis, both in basal and in autophagy-induced conditions. This mechanism is conserved in mammalian cells and in Drosophila, and requires the orthologous transcription factors Gli2 and Ci, respectively. Furthermore, we identify that activation of the Hedgehog pathway reduces PERK levels, concomitant with a decrease in phosphorylation of the translation initiation factor eukaryotic initiation factor 2α, suggesting a novel target of this pathway and providing a possible link between Hedgehog signalling and autophagy.

Edited by Noboru MizushimaKeywords: Autophagy-related gene 1 Unc-51 like kinase 1 Vps34 Jun-N-terminal kinase Target of rapamycin a b s t r a c t Drosophila has been shown to be a powerful model to study autophagy, whose regulation involves a core machinery consisting of Atg proteins and upstream signaling regulators similar to those in yeast and mammals. The conserved role in degrading proteins and organelles gives autophagy an important function in coordinating several cellular processes as well as in a number of pathological conditions. This review summarizes key studies in Drosophila autophagy research and discusses potential questions that may lead to better understanding of the roles and regulation of autophagy in higher eukaryotes.

No abstract