Regulation of the autophagy protein LC3 by phosphorylation

Cherra, Salvatore J.; Kulich, Scott; Uechi, Guy; Balasubramani, Manimalha; Mountzouris, John A.; Day, Billy W.; Chu, Charleen T.

doi:10.1083/jcb.201002108

Cited by 288 publications

(231 citation statements)

References 28 publications

Supporting

Mentioning

224

Contrasting

Order By: Relevance

“…Interestingly, LC3 is a direct substrate of PKA, and its phosphorylation prevents recruitment of LC3 to autophagosomes (Figure 2b). 26 Thus, DAPK and PKA target individual substrates, such as Beclin 1 and LC3 in autophagy.…”

Section: Modification Of Beclin 1 By Phosphorylation and Ubiquitinatimentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

View full text Add to dashboard Cite

Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP 3 R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy. Cell Death and Differentiation (2011) 18, 571-580; doi:10.1038/cdd.2010 published online 11 February 2011 Autophagy is an essential process that consists of selective degradation of cellular components. There are at least three different types of autophagy described and possibly more. These autophagy types include macroautophagy (hereafter referred to as autophagy), microautophagy and chaperonemediated autophagy. 1 The initial step of autophagy is the surrounding and sequestering of cytoplasmic organelles and proteins within an isolation membrane (phagophore). Potential sources for the membrane to generate the phagophore include the Golgi complex, endosomes, the endoplasmic reticulum (ER), mitochondria and the plasma membrane. 2 The nascent membranes are fused at their edges to form double-membrane vesicles, called autophagosomes. Autophagosomes undergo a stepwise maturation process, including fusion with acidified endosomal and/or lysosomal vesicles, eventually leading to the delivery of cytoplasmic contents to lysosomal components, where they fuse, then degrade and are recycled (Figure 1a). The process of mammalian autophagy is divided into six principal steps: initiation (Figure 1b It has been well demonstrated that autophagy depends on Atg5/Atg7, is associated with microtubule-associated protein light chain 3 (LC3) truncation and lipidation, and may originate directly from the ER membrane and other membrane organelles. Furthermore, recent study has identified a Atg5/Atg7-independent pathway of autophagy. 3 This pathway of autophagy was not associated with LC3 processing but appeared to involve autophagosome formation from late endosomes and the trans-Golgi. 3 Atg7-independent autophagy had been implicated in mitochondrial clearance from reticulocytes. 4 The exact molecular basis of Atg5/Atg7-independent autophagy remains to be elucidated. Interestingly, Beclin 1 is required for Atg5/Atg7-dependent and -independent autophagy. 3 However, the presence of Beclin 1-indep...

show abstract

Section: Modification Of Beclin 1 By Phosphorylation and Ubiquitinatimentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Instead, we observed reduced autophagy induction in cells transiently activating PKA (siRNA against Prkar1a), which correlates with the reported role of PKA in the negative regulation of autophagy. [39][40][41] This effect was, however, not observed in cells with a constitutively active PKA (genetic deletion), probably due to compensatory mechanisms.…”

Section: Discussionmentioning

confidence: 90%

A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

et al. 2016

View full text Add to dashboard Cite

The endoplasmic reticulum (ER) has a crucial role in the proper folding of proteins that are synthesized in the secretory pathway. Physiological and pathological conditions can induce accumulation of mis-or unfolded proteins in the ER lumen and thereby generate a state of cellular stress known as ER stress. The unfolded protein response aims at restoring protein-folding homeostasis, but turns into a toxic signal when ER stress is too severe or prolonged. ER stress-induced cellular dysfunction and death is associated with several human diseases, but the molecular mechanisms regulating death under unresolved ER stress are still unclear. We performed a siRNA-based screen to identify new regulators of ER stress-induced death and found that repression of the Carney complex-associated protein PRKAR1A specifically protected the cells from ER stress-induced apoptosis, and not from apoptosis induced by etoposide or TNF. We demonstrate that the protection results from PKA activation and associate it, at least in part, with the phosphorylation-mediated inhibition of the PKA substrate Drp1 (dynamin-related protein 1). Our results therefore provide new information on the complex regulation of cellular death under ER stress conditions and bring new insights on the conditions that regulate the pro-versus anti-death functions of PKA.

show abstract

“…This study may be a further indication of cAMP/PKA-signaling being able to negatively control autophagy in mammalian cells, presumably through PI3 0 K/mTOR activation 38 or direct PKA mediated phosphorylation of the autophagosome associated factor microtubule-associated protein-1 light chain-3 (LC3). 39 However, this requires substantiating experimentally especially in regard to identifying a PKA target in the complex autophagic machinery, 40 that when phosphorylated has an inhibitory role to block the autophagic process. These data also raise doubt for the notion that 3-MA inhibits autophagy exclusively via specific phosphatidylinositol 3 0 -kinase (PI3 0 K) inhibition.…”

Section: Discussionmentioning

confidence: 99%

Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets

Boland

Alarcón

Ali

et al. 2015

Islets

View full text Add to dashboard Cite

(2015) Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets, Islets, 7:2, e1073435, DOI: 10.1080DOI: 10. /19382014.2015 To link to this article: https://doi.org/10. 1080/19382014.2015 Abbreviations: 3-MA, 3-methyladenine; N6-MA, N6-methyladenine; 9-MA, 9-methyladenine; 1-MA, 1-methyladenine; 7-MA, 7-methyladenine; PKA, protein kinase-A; CREB, cAMP-response element binding protein; 9-CPA, 9-cylopentyladenine; PDE, phosphodiesterase; IBMX, 3-isobutyl-1-methylxanthine; GPR-40, G-protein coupled receptor-40; PLC, phospholipase-C; DAG, diacylglycerol; PKC, protein kinase-C; GLP-1, glucagon-like peptide-1; GIP, gastric inhibitory peptide; MMPX, 8-Methoxymethyl-3-isobutyl-1-methyl xanthine; EHNA, Erythro-9-(2-hydroxy-3-nonyl) adenine; KRBH, Krebs-Ringer bicarbonate buffer; PMSF, phenylmethylsulfonyl fluoride; TLCK, Tosyl-lysyl chloromethylketone; RIA, radioimmunoassay; BCA, bicinchoninic acid; LC3, Microtubule-associated protein-1 light chain-3; mTOR, mammalian Target of Rapamycin; PI3 0 K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PDK-1, Phosphoinositide dependent kinase-1; AMPK, AMP-activated protein kinase.Monomethyladenines have effects on DNA repair, G-protein-coupled receptor antagonism and autophagy. In islet û-cells, 3-methyladenine (3-MA) has been implicated in DNA-repair and autophagy, but its mechanism of action is unclear. Here, the effect of monomethylated adenines was examined in rat islets. 3-MA, N6-methyladenine (N6-MA) and 9-methyladenine (9-MA), but not 1-or 7-monomethylated adenines, specifically potentiated glucose-induced insulin secretion (3-4 fold; p 0.05) and proinsulin biosynthesis (»2-fold; p 0.05). Using 3-MA as a 'model' monomethyladenine, it was found that 3-MA augmented [cAMP] i accumulation (2-3 fold; p 0.05) in islets within 5 minutes. The 3-, N6-and 9-MA also enhanced glucose-induced phosphorylation of the cAMP/protein kinase-A (PKA) substrate cAMP-response element binding protein (CREB). Treatment of islets with pertussis or cholera toxin indicated 3-MA mediated elevation of [cAMP] i was not mediated via G-protein-coupled receptors. Also, 3-MA did not compete with 9-cyclopentyladenine (9-CPA) for adenylate cyclase inhibition, but did for the pan-inhibitor of phosphodiesterase (PDE), 3-isobutyl-1-methylxanthine (IBMX). Competitive inhibition experiments with PDE-isoform specific inhibitors suggested 3-MA to have a preference for PDE4 in islet û-cells, but this was likely reflective of PDE4 being the most abundant PDE isoform in û-cells. In vitro enzyme assays indicated that 3-, N6-and 9-MA were capable of inhibiting most PDE isoforms found in û-cells. Thus, in addition to known inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 0 K)/m Target of Rapamycin (mTOR) signaling, 3-MA also acts as a pan-phosphodiesterase inhibitor in pancreatic û-cells to elevate [cAMP] i and then potentiate glucose-induced insulin secretion and production in parallel.

show abstract

Regulation of the autophagy protein LC3 by phosphorylation

Abstract: PKA puts the brakes on autophagy by inhibiting LC3 recruitment to autophagosomes.

Cited by 288 publications

References 28 publications

The Beclin 1 network regulates autophagy and apoptosis

The Beclin 1 network regulates autophagy and apoptosis

A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets

Contact Info

Product

Resources

About