Regulation of Autophagy by Protein Phosphorylation

Stork, Björn; Alers, Sebastian; Löffler, Antje S.; Wesselborg, Sebastian

doi:10.5772/48502

Cited by 6 publications

(3 citation statements)

References 195 publications

(354 reference statements)

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“…Regulation of phagophore initiation is highly dependent on phosphorylation events ( Stork et al, 2012 ). For example, increased phosphorylation of ULK1 kinase substrates promotes autophagy initiation and elongation.…”

Section: Discussionmentioning

confidence: 99%

Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator

Jung

Nayak

Schaeffer

et al. 2017

eLife

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Autophagy is an intracellular recycling and degradation pathway that depends on membrane trafficking. Rab GTPases are central for autophagy but their regulation especially through the activity of Rab GEFs remains largely elusive. We employed a RNAi screen simultaneously monitoring different populations of autophagosomes and identified 34 out of 186 Rab GTPase, GAP and GEF family members as potential autophagy regulators, amongst them SMCR8. SMCR8 uses overlapping binding regions to associate with C9ORF72 or with a C9ORF72-ULK1 kinase complex holo-assembly, which function in maturation and formation of autophagosomes, respectively. While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus. Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2. Collectively, we established SMCR8 as multifaceted negative autophagy regulator.DOI: http://dx.doi.org/10.7554/eLife.23063.001

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Section: Discussionmentioning

confidence: 99%

Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator

Jung

Nayak

Schaeffer

et al. 2017

eLife

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“…Furthermore, epimastigotes over-expressing TcAMPKα2 were able to reach higher autophagic activity during prolonged nutritional stress, in comparison with control lines. Autophagy is an essential process in the progression of the life cycle of trypanosomatids [41,54,55] and AMPK is known to be involved in these processes in an ancestral and conserved manner [21,22,[56][57][58][59]. We hypothesize that TcAMPKα2 would induce the autophagy process to cope with the nutritional stress caused by the absence of glucose as an energy source.…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi

Sternlieb¹,

Schoijet

Genta³

et al. 2021

PLoS Negl Trop Dis

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Trypanosoma cruzi, the etiological agent of Chagas disease, has a digenetic life cycle. In its passage from the insect vector to the mammalian host, and vice versa, it must be prepared to cope with abrupt changes in environmental conditions, such as carbon source, pH, temperature and osmolarity, in order to survive. Sensing and signaling pathways that allow the parasite to adapt, have unique characteristics with respect to their hosts and other free-living organisms. Many of the canonical proteins involved in these transduction pathways have not yet been found in the genomes of these parasites because they present divergences either at the functional, structural and/or protein sequence level. All of this makes these pathways promising targets for therapeutic drugs. The AMP-activated protein kinase (AMPK) is a serine/threonine kinase activated by environmental stresses such as osmotic stress, hypoxia, ischaemia and exercise that results in reduction of ATP and increase of AMP levels. Thus, AMPK is regarded as a fuel gauge, functioning both as a nutrient and an energy sensor, to maintain energy homeostasis and, eventually, to protect cells from death by nutrient starvation. In the present study we report the characterization of AMPK complexes for the first time in T. cruzi and propose the function of TcAMPK as a novel regulator of nutritional stress in epimastigote forms. We show that there is phosphotransferase activity specific for SAMS peptide in epimastigotes extracts, which is inhibited by Compound C and is modulated by carbon source availability. In addition, TcAMPKα2 subunit has an unprecedented functional substitution (Ser x Thr) at the activation loop and its overexpression in epimastigotes led to higher autophagic activity during prolonged nutritional stress. Moreover, the over-expression of the catalytic subunits resulted in antagonistic phenotypes associated with proliferation. Together, these results point to a role of TcAMPK in autophagy and nutrient sensing, key processes for the survival of trypanosomatids and for its life cycle progression.

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“…Autophagy consists of several stages, such as initiation, expansion, autophagosome formation, autophagosome-lysosome fusion, and degradation. Each of these steps can be dynamically regulated via a complex network of autophagy-relevant proteins and by posttranslational modifiers including kinases (Stork et al, 2012). It has been suggested that HIPK2 overexpression promotes phagophore expansion and increases mature autophagosome formation in liver sepsis (Jiang et al, 2018).…”

Section: Figure 4 | Continuedmentioning

confidence: 99%

HIPK2 Is Required for Midbody Remnant Removal Through Autophagy-Mediated Degradation

Sardina

Monteonofrio

Ferrara

et al. 2020

Front. Cell Dev. Biol.

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At the end of abscission, the residual midbody forms the so-called midbody remnant (MBR), a platform affecting cell fate with emerging key role in differentiation, development, and tumorigenicity. Depending on cell type and pathophysiological context, MBRs undergo different outcomes: they can be retained, released, internalized by nearby cells, or removed through autophagy-mediated degradation. Although mechanisms underlying MBR formation, positioning, and processing have been recently identified, their regulation is still largely unknown. Here, we report that the multifunctional kinase HIPK2 regulates MBR processing contributing to MBR removal. In the process of studying the role of HIPK2 in abscission, we observed that, in addition to cytokinesis failure, HIPK2 depletion leads to significant accumulation of MBRs. In particular, we detected comparable accumulation of MBRs after HIPK2 depletion or treatment with the autophagic inhibitor chloroquine. In contrast, single depletion of the two independent HIPK2 abscission targets, extrachromosomal histone H2B and severing enzyme Spastin, only marginally increased MBR retention, suggesting that MBR accumulation is not just linked to cytokinesis failure. We found that HIPK2 depletion leads to (i) increased levels of CEP55, a key effector of both midbody formation and MBR degradation; (ii) decreased levels of the selective autophagy receptors NBR1 and p62/SQSTM1; and (iii) impaired autophagic flux. These data suggest that HIPK2 contributes to MBR processing by regulating its autophagy-mediated degradation.

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Regulation of Autophagy by Protein Phosphorylation

Cited by 6 publications

References 195 publications

Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator

Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator

An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi

HIPK2 Is Required for Midbody Remnant Removal Through Autophagy-Mediated Degradation

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