Autophagy regulates the cell cycle of murine HSPCs in a nutrient-dependent manner

Cao, Yan; Zhang, Aihong; Cai, Jinyang; Yuan, Na; Wei, Lin; Liu, Shengbing; Xu, Fei; Lin, Shiu‐Ru; Li, Xin; Fang, Yixuan; Zhen, Wang; Wang, Zhijian; Wang, Jian; Zhang, Han; Zhao, Wei‐Li; Hu, Shaoyan; Zhang, Suping; Wang, Jianrong

doi:10.1016/j.exphem.2014.11.002

Cited by 29 publications

(22 citation statements)

References 44 publications

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“…39,40 Here we confirm the presence of many autophagyrelated proteins in platelets. Using transgenic mice expressing GFP-fused LC3, Beclin 1, and Atg5, we further show that these autophagy markers ;PF4-Cre/1 (iv-vi) mice.…”

Section: Discussionsupporting

confidence: 80%

“…85 Moreover, another work using hematopoietic system conditional Atg7 knockout (ie, Atg7 f/f ;Vav-Cre) mice was published that demonstrates that in addition to severe defects in megakaryogenesis, megakaryocyte differentiation and thrombopoiesis observed in these mice, platelets isolated from these mice are defective in activation and aggregation. 39 Our work using Atg7 f/f ;PF4-Cre mice, which deletes the Atg7 genes at a later stage in platelet production, distinguishes the roles of autophagy in platelets and in hemostasis from roles in megakaryogenesis and in megakaryocyte differentiation.…”

Section: Autophagy In Hemostasis and Thrombosis 1229mentioning

confidence: 99%

“…Because PF4-Cre expression deletes the floxed Atg7 gene at a later stage of megakaryocyte differentiation, 46 it is possible that bleeding in Atg7 f/f ;PF4-Cre/1 mice is a result of defective platelet production, especially given the thrombocytopenia phenotype of the Atg7 f/f ;Vav-Cre/1 mice, where Atg7 is deleted at an earlier stage of the hematopoietic cell lineage. 39 To investigate this possibility, we measured platelet counts and mean platelet volumes as metrics of thrombocytopenia and faulty platelet production. Compared with Atg7 f/f mice, Atg7 f/f ;PF4-Cre/1 mice had indistinguishable platelet counts ( Figure 6C) and mean platelet volumes ( Figure 6D), suggesting that defects in Atg7-mediated platelet function or functions, but not thrombocytopenia, accounted for the severe bleeding in Atg7 f/f ;PF4-Cre/1 mice.…”

Section: Deletion Of Atg7 In Platelets Leads To Impaired Hemostasis Amentioning

confidence: 99%

“…Only recently, a role for autophagy in megakaryopoiesis and thrombopoiesis was indicated in a study on hematopoietic lineage-specific Atg7 deletion mice carrying Vav promoter-driven Cre. 39 Feng et al reported starvation/rapamycininduced autophagy in platelets. 40 They also found that platelets isolated from whole-body heterozygous Becn1 knockout mice are defective in ex vivo collagen-induced aggregation, as well as flow-based platelet adhesion and thrombus formation.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

Ouseph

Huang

Banerjee

et al. 2015

Blood

121

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Key Points• Autophagy, an essential degradation pathway, is constitutively active in resting platelets and is induced upon platelet activation.• Platelet autophagy is indispensable for hemostasis and thrombus formation.Autophagy is important for maintaining cellular homeostasis, and thus its deficiency is implicated in a broad spectrum of human diseases. Its role in platelet function has only recently been examined. Our biochemical and imaging studies demonstrate that the core autophagy machinery exists in platelets, and that autophagy is constitutively active in resting platelets. Moreover, autophagy is induced upon platelet activation, as indicated by agonist-induced loss of the autophagy marker LC3II. Additional experiments, using inhibitors of platelet activation, proteases, and lysosomal acidification, as well as platelets from knockout mouse strains, show that agonist-induced LC3II loss is a consequence of platelet signaling cascades and requires proteases, acidic compartments, and membrane fusion. To assess the physiological role of platelet autophagy, we generated a mouse strain with a megakaryocyte-and platelet-specific deletion of Atg7, an enzyme required for LC3II production. Ex vivo analysis of platelets from these mice shows modest defects in aggregation and granule cargo packaging. Although these mice have normal platelet numbers and size distributions, they exhibit a robust bleeding diathesis in the tail-bleeding assay and a prolonged occlusion time in the FeCl 3 -induced carotid injury model. Our results demonstrate that autophagy occurs in platelets and is important for hemostasis and thrombosis. (Blood. 2015;126(10):1224-1233 Introduction Autophagy, one of the major degradation pathways in eukaryotes, is important for cellular homeostasis and is implicated in a broad spectrum of human diseases including cancer, neurodegeneration, and cardiovascular diseases.1 There are 3 main types: chaperone-mediated autophagy, 2 microautophagy, 3,4 and the primary form, macroautophagy (referred to hereafter as autophagy).5 Autophagy involves de novo synthesis of double-membraned organelles called autophagosomes that contain cytosolic constituents including damaged organelles (eg, mitochondria) and protein aggregates. Autophagosomes fuse with multivesicular bodies, late endosomes, and lysosomes to form autolysosomes, 6 in which waste elimination, energy production, and recycling of cellular components take place.Autophagosome biogenesis and maturation use several protein complexes. [7][8][9][10] In mammals, cellular signals (eg, starvation) activate the Ulk1 complex (Ulk1, FIP200, Atg13, and Atg101), 11-14 which together with syntaxin 17, 15 localizes Atg14/Atg14L [16][17][18][19] to the endoplasmic reticulum. 15,20 This recruits the Beclin 1-Vps34 core complex (Beclin 1, Vps34, and Vps15) to autophagosome initiation sites and promotes phosphatidylinositol 3-phosphate production for recruitment of additional autophagy pathway components.20,21 Two ubiquitin-like conjugation systems are also important for autoph...

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Section: Discussionsupporting

confidence: 80%

Section: Autophagy In Hemostasis and Thrombosis 1229mentioning

confidence: 99%

Section: Deletion Of Atg7 In Platelets Leads To Impaired Hemostasis Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

Ouseph

Huang

Banerjee

et al. 2015

Blood

121

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“…However, whether the observed proliferation is a consequence of the cytopenias or cell intrinsic is still unclear. In support of the cell-intrinsic hypothesis is a study showing autophagic signaling associated with ubiquitinmediated degradation of cyclin-D3 in HSPCs under nutrient stress [35]. However, the evidence presented for this is solely based on pharmacological inhibition of autophagy and therefore should be interpreted with caution.…”

Section: Proteostasismentioning

confidence: 99%

Mechanistic roles of autophagy in hematopoietic differentiation

Riffelmacher

Simon

2016

The FEBS Journal

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Autophagy is increasingly recognized for its active role in development and differentiation. In particular, its role in the differentiation of hematopoietic cells has been extensively studied, likely because blood cells are accessible, easy to identify and purify, and their progenitor tree is well defined. This review aims to discuss the mechanisms by which autophagy impacts on differentiation, using hematopoietic cell types as examples. Autophagy's roles include the remodeling during terminal differentiation, the maintenance of a long-lived cell type, and the regulation of the balance between selfrenewal and quiescence in stem-like cells. We discuss and compare the mechanistic roles of autophagy, such as prevention of apoptosis, supply of energy metabolites and metabolic adaption, and selective degradation of organelles and of regulatory factors.

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How autophagy can restore proteostasis defects in multiple diseases?

Joshi

Upadhyay

Prajapati

et al. 2020

Medicinal Research Reviews

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Cellular evolution develops several conserved mechanisms by which cells can tolerate various difficult conditions and overall maintain homeostasis. Autophagy is a well‐developed and evolutionarily conserved mechanism of catabolism, which endorses the degradation of foreign and endogenous materials via autolysosome. To decrease the burden of the ubiquitin‐proteasome system (UPS), autophagy also promotes the selective degradation of proteins in a tightly regulated way to improve the physiological balance of cellular proteostasis that may get perturbed due to the accumulation of misfolded proteins. However, the diverse as well as selective clearance of unwanted materials and regulations of several cellular mechanisms via autophagy is still a critical mystery. Also, the failure of autophagy causes an increase in the accumulation of harmful protein aggregates that may lead to neurodegeneration. Therefore, it is necessary to address this multifactorial threat for in‐depth research and develop more effective therapeutic strategies against lethal autophagy alterations. In this paper, we discuss the most relevant and recent reports on autophagy modulations and their impact on neurodegeneration and other complex disorders. We have summarized various pharmacological findings linked with the induction and suppression of autophagy mechanism and their promising preclinical and clinical applications to provide therapeutic solutions against neurodegeneration. The conclusion, key questions, and future prospectives sections summarize fundamental challenges and their possible feasible solutions linked with autophagy mechanism to potentially design an impactful therapeutic niche to treat neurodegenerative diseases and imperfect aging.

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Autophagy regulates the cell cycle of murine HSPCs in a nutrient-dependent manner

Cited by 29 publications

References 44 publications

Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

Mechanistic roles of autophagy in hematopoietic differentiation

How autophagy can restore proteostasis defects in multiple diseases?

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