Beclin 1 Forms Two Distinct Phosphatidylinositol 3-Kinase Complexes with Mammalian Atg14 and UVRAG

Itakura, Eisuke; Kishi, Chieko; Inoue, Kinji; Mizushima, Noboru

doi:10.1091/mbc.e08-01-0080

Cited by 1,026 publications

(1,109 citation statements)

References 74 publications

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“…In yeast, the autophagy-specific PI3K complex is composed of four proteins: Vps34 (catalytic unit), Vps15, Atg6/Vps30, and Atg14 [31]. In mammals, Beclin 1 [32,33] and Atg14L/Barkor [34][35][36][37] are identified as the orthologues of Atg6/Vps30 and Atg14, respectively. It is thought that the production of PI3P is initiated by the dot-like accumulation of the Atg14/Atg14L-containing PI3K complex at the PAS (in yeast) or on the endoplasmic reticulum (ER) (in mammals; discussed below).…”

Section: The Atg1/ulk Complexmentioning

confidence: 99%

A current perspective of autophagosome biogenesis

2013

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Autophagy is a bulk degradation system induced by cellular stresses such as nutrient starvation. Its function relies on the formation of double-membrane vesicles called autophagosomes. Unlike other organelles that appear to stably exist in the cell, autophagosomes are formed on demand, and once their formation is initiated, it proceeds surprisingly rapidly. How and where this dynamic autophagosome formation takes place has been a long-standing question, but the discovery of Atg proteins in the 1990's significantly accelerated our understanding of autophagosome biogenesis. In this review, we will briefly introduce each Atg functional unit in relation to autophagosome biogenesis, and then discuss the origin of the autophagosomal membrane with an introduction to selected recent studies addressing this problem.

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Section: The Atg1/ulk Complexmentioning

confidence: 99%

A current perspective of autophagosome biogenesis

2013

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“…This complex recruits the protein complexes required to nucleate the autophagosomes into a structure known as phagophore assembly site (PAS). The class-III PI3K, also known as vacuolar protein sorting 34 (Vps34), Atg14, and Beclin 1 (Atg6 in yeast) form another complex that is also required for this process (Itakura et al 2008). The Vps34 and the Atg1 complexes recruit proteins involved in two ubiquitin-like conjugation systems that elongate and shape the autophagosome membrane around the substrate: the E1-like protein Atg7 catalyzes the covalent linkage of Atg12 to the E2-like Atg10, which then transfers Atg12 to Atg5, forming the Atg5-12 complex (Geng and Klionsky 2008).…”

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p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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“…8 Through its interaction with class III phosphatidyl-inositol-3-phosphate kinase (PI3kIII/ Vps34), beclin-1 (also known as atg6/Vps30) regulates autophagy. 9,10 Autophagy is a lysosomaldependent pathway for macromolecular and organelle degradation that has a pivotal role in cell homeostasis. 11 Autophagy begins with the entrapment of the substrate (protein aggregates, aged and oxidized membranes or organelles) by a multilayered membrane originated in the proximity of the endoplasmic reticulum and trans Golgi network.…”

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Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas

Nicotra

Mercalli

Peracchio³

et al. 2010

Modern Pathology

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The expression of beclin-1, an oncosuppressor monoallelically deleted in 460% epithelial cancers, has been shown to be developmentally regulated in T and B lymphocytes. By interacting with either bcl-2 or class III phosphatidyl-inositol-3-phosphate kinase, beclin-1 regulates apoptosis and autophagy, two processes crucial for lymphatic tissue homeostasis. We analyzed the potential link between beclin-1-mediated autophagy and the malignant behaviour of lymphomas. The tissue expression of beclin-1 was analyzed in a large series of nonHodgkin lymphomas and correlated with patient's clinical outcome. By immunofluorescence, beclin-1 staining showed faintly detectable and diffusely distributed in the cytoplasm (regarded as negative) or confined to the perinuclear region as large and brilliant puncta suggestive of macro-aggregate reactivity (regarded as positive). The positive expression of beclin-1 well correlated with the presence of LC3-positive autophagic vacuoles and was inversely correlated with the expression of bcl-2. Non-Hodgkin lymphomas in which X20% of tumour cells expressed high level of beclin-1 aggregates were associated with a complete (57%) or partial (35%) remission. The 5-year overall survival probability, calculated by the Kaplan-Meier method, was 92% and 42% in beclin-1-expressing non-Hodgkin lymphomas with X20% and o20% positive cells, respectively (log-rank test, Po0.000.1). In Cox multivariate analysis, the level of beclin-1 expression, adjusted for patient's age and pathologic stage, revealed to be significantly correlated with patient's survival (Po0.0001). This is the first demonstration of the involvement of beclin-1 and autophagy in the clinical behaviour of non-Hodgkin lymphomas. The present data are compatible with the hypothesis that non-Hodgkin lymphomas with upregulated autophagy are more responsive to chemotherapy and indicate that beclin-1 could be a valuable independent prognostic factor in this heterogeneous group of tumours. Modern Pathology (2010) 23, 937-950;

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Beclin 1 Forms Two Distinct Phosphatidylinositol 3-Kinase Complexes with Mammalian Atg14 and UVRAG

Cited by 1,026 publications

References 74 publications

A current perspective of autophagosome biogenesis

A current perspective of autophagosome biogenesis

p62/SQSTM1 at the interface of aging, autophagy, and disease

Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas

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