The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis

Joo, Joung Hyuck; Wang, Bo; Frankel, Elisa B.; Ge, Liang; Xu, Lu; Iyengar, Rekha; Li-Harms, Xiu Jie; Wright, C. David; Shaw, Timothy I.; Lindsten, Tullia; Green, Douglas R.; Peng, Junmin; Hendershot, Linda M.; Kilic, Fusun; Sze, Ji Ying; Audhya, Anjon; Kundu, Mondira

doi:10.1016/j.molcel.2016.04.020

Cited by 155 publications

(105 citation statements)

References 61 publications

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“…Constitutive autophagy involves genes from the ubiquitin-like conjugation pathway (e.g., Atg5 and Atg7 ) and Fip200/Atg17 [35–37]. However, in the CNS it proceeds in the absence of Ulk1 and Ulk2 [38••]. In the absence of exogenous stress, ULK/ATG1 regulates endoplasmic reticulum (ER)-to-Golgi trafficking of specific cargo in Caenorhabditis elegans and mammalian cells [38••].…”

Section: Ulk/atg1 Regulates Er-to-golgi Traffickingmentioning

confidence: 99%

Canonical and noncanonical functions of ULK/Atg1

Wang

Kundu

2017

Current Opinion in Cell Biology

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Mammalian Unc-51–like kinases 1 and 2 (ULK1 and ULK2) belong to the ULK/Atg1 family of serine/threonine kinases, which are conserved from yeast to mammals. Although ULK/Atg1 is best known for regulating flux through the autophagy pathway, it has evolutionarily conserved noncanonical functions in protein trafficking that are essential for maintaining cellular homeostasis. As a direct target of energy- and nutrient-sensing kinases, ULK/Atg1 is positioned to regulate the distribution and use of cellular resources in response to metabolic cues. In this review, we provide an overview of the molecular mechanisms through which ULK/Atg1 carries out its canonical and noncanonical functions and the signaling pathways that link its function to metabolism. We also highlight potential contributions of ULK/Atg1 in human diseases, including cancer and neurodegeneration.

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Section: Ulk/atg1 Regulates Er-to-golgi Traffickingmentioning

confidence: 99%

Canonical and noncanonical functions of ULK/Atg1

Wang

Kundu

2017

Current Opinion in Cell Biology

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“…Conjugation of Atg8/LC3 family proteins to phosphatidylethanolamine, known as “LC3 lipidation” for short, is the hallmark downstream reaction driven by these proteins. These Atg proteins were discovered for their roles in autophagy and are primarily dedicated to this function, although “moonlighting” roles in non-autophagic functions have been reported (18). Multipurpose membrane trafficking factors also have essential roles in the pathway.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Autophagy Initiation

Hurley

Young

2017

Annu. Rev. Biochem.

531

424

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Autophagy is the process of cellular self-eating by a double-membrane organelle, the autophagosome. A range of signaling processes converge on two protein complexes to initiate autophagy: the ULK1 protein kinase complex and the PI3KC3-C1 lipid kinase complex. Some 90 % of the mass of these large protein complexes consists on non-catalytic domains and subunits, and the ULK1 complex has essential non-catalytic activities. Structural studies of these complexes have shed increasing light on the regulation of their catalytic and non-catalytic activities in autophagy initiation. The autophagosome is thought to nucleate from vesicles containing the integral membrane protein Atg9, COPII vesicles, and possibly other sources. In the wake of reconstitution and superresolution imaging studies, we are beginning to understand how the ULK1 and PI3KC3-C1 complexes might coordinate the nucleation and fusion of Atg9 and COPII vesicles at the start of autophagosome biogenesis.

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“…In particular, conditional deletion of Atg7 results in massive neuronal death, behavioral impairments, and accumulation of intracellular Aβ (Komatsu et al., 2006; Komatsu, Wang et al., 2007; Nilsson, Loganathan, Sekiguchi, Matsuba, & Hui, 2013), while Atg17 ‐null neuronal cells suffer progressive loss and aggregation of proteotoxins as well (Liang, Wang, Peng, Gan, & Guan, 2010). Moreover, conditional deficiency of Ulk1 in the central nervous system also results in neuronal loss and degeneration, which normally serves as a key kinase triggering the formation of PI3P (Joo, Wang, Frankel, Ge, & Xu, 2016) (Table 2). Overall, all these evidence confirm that dysregulation of autophagy may closely and positively correlate to the pathogenesis of AD.…”

Section: Pathological Association Between Autophagic Pathways and Alzmentioning

confidence: 99%

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

et al. 2018

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Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

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The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis

Cited by 155 publications

References 61 publications

Canonical and noncanonical functions of ULK/Atg1

Canonical and noncanonical functions of ULK/Atg1

Mechanisms of Autophagy Initiation

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

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