Phospholipase D1 is an effector of Rheb in the mTOR pathway

Sun, Yu; Fang, Yimin; Yoon, Mee-Sup; Zhang, C.; Roccio, Marta; Zwartkruis, Fried; Armstrong, Michelle D.; Brown, H. Alex; Chen, Jiawen

doi:10.1073/pnas.0712268105

Cited by 160 publications

(160 citation statements)

References 41 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…It has been suggested that PA exerted its signaling actions as a second messenger through regulating mTOR and other proteins in the mTOR pathway. 26,27 An earlier study by Moreau et al 28 showed that a small G-protein, Arf6, facilitated AP biogenesis via inducing PLD activity.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

et al. 2014

View full text Add to dashboard Cite

Many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by abnormal accumulations of aggregated proteins. Brains in these diseases also show accumulation of autophagic vesicles in the neuronal cytoplasm, suggesting impairment of the autophagic process. As autophagy involves de novo membrane production and vesicle fusion, extensive changes in lipid molecules are necessary. However, the involvement of signaling lipid-modifying enzymes in autophagy and their roles in neurodegenerative diseases are not clear. Using specific inhibitor, we show that loss of phospholipase D1 (PLD1) activity resulted in an accumulation of microtubule-associated protein light chain 3 (LC3), p62, and polyubiquitinated proteins, signs representing malfunction in autophagic flux. Fluorescence and electron microscopic analyses demonstrated impaired fusion of autophagosomes with lysosomes, resulting in accumulation of autophagosomes. Within the cells with impaired autophagic flux, a-synuclein aggregates accumulated in autophagosomes. Knockdown of PLD1 expression using small interfering RNA also resulted in impaired autophagic flux and accumulation of a-synuclein aggregates in autophagosomes. Neuronal toxicity caused by a-synuclein accumulation was rescued by overexpression of PLD1; however, expression of activity-deficient mutant, PLD1-KRM, showed reduced rescue effects. Finally, we demonstrated that both PLD activity and expression levels were reduced in brain tissues of dementia with Lewy bodies (DLB) patients, whereas the amounts of a-synuclein and p62 were increased in the same tissue samples. Collectively, these results suggest that insufficient PLD activity, and therefore, the changes in phospholipid compositions within membranes, might be an important contributor to impaired autophagic process and protein accumulation in Lewy body diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Most recently, our studies have uncovered a direct interaction between Rheb and PLD1. 35 We have found that PLD1 and PA are required for the activation of mTORC1 by overexpressed Rheb, and that PLD is also involved in mTORC1 activation induced by depletion or deletion of TSC2. 35 In addition, mitogenic activation of PLD is dampened by Rheb knockdown or TSC2 overexpression, 35 suggesting that TSC-Rheb is an indispensable upstream regulator of PLD.…”

Section: Pld1 As An Effector Of Rheb In Mtorc1 Signalingmentioning

confidence: 98%

“…35 We have found that PLD1 and PA are required for the activation of mTORC1 by overexpressed Rheb, and that PLD is also involved in mTORC1 activation induced by depletion or deletion of TSC2. 35 In addition, mitogenic activation of PLD is dampened by Rheb knockdown or TSC2 overexpression, 35 suggesting that TSC-Rheb is an indispensable upstream regulator of PLD. Consistently, serum-activation of PLD is perturbed by pharmacological modulation of AMPK and PI3K, 35 both upstream regulators of TSC2.…”

Section: Pld1 As An Effector Of Rheb In Mtorc1 Signalingmentioning

confidence: 98%

“…34), whereas PLD knockdown blocks mitogenic activation of mTORC1 signaling. 32,35,36 The small G protein Cdc42 had long been known as an activator of S6K1 with an exact mechanism yet to be determined, 37 and now PLD1 has been revealed as a molecular link between Cdc42 and mTORC1. 32 In addition to PLD, two other PA-producing enzymes-lysophosphatidic acid acyltransferase (LPAAT) and diacylglycerol kinase (DGK)-have also been shown to regulate mTOR signaling through PA, 38,39 further validating the link between PA and mTOR.…”

Section: Phosphatidic Acid and Phospholipase D In Mtorc1 Signalingmentioning

confidence: 99%

See 1 more Smart Citation

mTOR signaling: PLD takes center stage

Sun¹,

Chen

2008

Cell Cycle

View full text Add to dashboard Cite

“…Rheb indirectly activates mTORC1 by stimulating PLD1 to produce the lipid, phosphatidic acid (PA) (Sun et al, 2008).…”

Section: Pld1mentioning

confidence: 99%

Rheb in neuronal degeneration, regeneration, and connectivity

Potheraveedu

Schöpel

Stoll

et al. 2017

Biological Chemistry

View full text Add to dashboard Cite

Abstract:The small GTPase Rheb was originally detected as an immediate early response protein whose expression was induced by NMDA-dependent synaptic activity in the brain. Rheb's activity is highly regulated by its GTPase activating protein (GAP), the tuberous sclerosis complex protein, which stimulates the conversion from the active, GTP-loaded into the inactive, GDP-loaded conformation. Rheb has been established as an evolutionarily conserved molecular switch protein regulating cellular growth, cell volume, cell cycle, autophagy, and amino acid uptake. The subcellular localization of Rheb and its interacting proteins critically regulate its activity and function. In stem cells, constitutive activation of Rheb enhances differentiation at the expense of self-renewal partially explaining the adverse effects of deregulated Rheb in the mammalian brain. In the context of various cellular stress conditions such as oxidative stress, ER-stress, death factor signaling, and cellular aging, Rheb activation surprisingly enhances rather than prevents cellular degeneration. This review addresses cell type-and cell state-specific function(s) of Rheb and mainly focuses on neurons and their surrounding glial cells. Mechanisms will be discussed in the context of therapy that interferes with Rheb's activity using the antibiotic rapamycin or low molecular weight compounds.

show abstract

Phospholipase D1 is an effector of Rheb in the mTOR pathway

Cited by 160 publications

References 41 publications

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

mTOR signaling: PLD takes center stage

Rheb in neuronal degeneration, regeneration, and connectivity

Contact Info

Product

Resources

About