Life Sciences Research for Lifelong Health

Nicholas Ktistakis

Research Summary

Autophagy (from the Greek self-eating) is a cellular mechanism which generates nutrients for the cell, primarily during times of starvation. Autophagy is also used to eliminate cell material that becomes damaged, leading to a periodic clean-up of the cell interior. Although it is a response by single cells, it is also very important for the health of an organism.

When autophagy is suppressed cells exhibit signs of oxidative damage because their dysfunctional mitochondria cannot be removed and continue to produce reactive oxygen species. Similarly, suppression of autophagy causes the build-up of mutant proteins that cause neurodegenerative disorders.

Autophagy is also critical for the neonatal period: animals which lack autophagy die soon after birth because they cannot generate nutrients during that time. Finally, autophagy is critical for the extension of lifespan in all organisms studied, and is therefore a significant factor that affects healthy ageing. The pathway of autophagy starts when a novel double membrane vesicle called an autophagosome is formed in the cell interior.

We have shown that one of the signals for formation of autophagosomes is the synthesis of a lipid called PI3P which leads to formation of omegasomes. These are membrane extensions of the endoplasmic reticulum, from which some autophagosomes emerge. We are studying exactly how this happens, both in terms of signals and of how the intermediate structures eventually lead to an autophagosome.

Latest Publications

An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis.
Odle RI, Walker SA, Oxley D, Kidger AM, Balmanno K, Gilley R, Okkenhaug H, Florey O, Ktistakis NT, Cook SJ

Since nuclear envelope breakdown occurs during mitosis in metazoan cells, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. However, repression of macroautophagy during mitosis remains controversial and mechanistic detail limited to the suggestion that CDK1 phosphorylates VPS34. Here, we show that initiation of macroautophagy, measured by the translocation of the ULK complex to autophagic puncta, is repressed during mitosis, even when mTORC1 is inhibited. Indeed, mTORC1 is inactive during mitosis, reflecting its failure to localize to lysosomes due to CDK1-dependent RAPTOR phosphorylation. While mTORC1 normally represses autophagy via phosphorylation of ULK1, ATG13, ATG14, and TFEB, we show that the mitotic phosphorylation of these autophagy regulators, including at known repressive sites, is dependent on CDK1 but independent of mTOR. Thus, CDK1 substitutes for inhibited mTORC1 as the master regulator of macroautophagy during mitosis, uncoupling autophagy regulation from nutrient status to ensure repression of macroautophagy during mitosis.

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Molecular cell, , 1097-4164, , 2019

PMID: 31733992

Autophagosome biogenesis machinery.
Walker SA, Ktistakis NT

We review current knowledge of the process of autophagosome formation with special emphasis on the very early steps: turning on the autophagy pathway, assembling the autophagy machinery, and building the autophagosome. The pathway is remarkably well co-ordinated spatially and temporally, and it shows broad conservation across species and cell types, including neurons. In addition, although much current knowledge derives mostly from settings of non-selective autophagy, recent work also indicates that selective autophagy, and more specifically mitophagy, shows similar dynamics. Having an understanding of this remarkable process may help the design of novel therapeutics for neurodegeneration and other pathologies.

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Journal of molecular biology, , 1089-8638, , 2019

PMID: 31705882

Targeting of early endosomes by autophagy facilitates EGFR recycling and signalling.
Fraser J, Simpson J, Fontana R, Kishi-Itakura C, Ktistakis NT, Gammoh N

Despite recently uncovered connections between autophagy and the endocytic pathway, the role of autophagy in regulating endosomal function remains incompletely understood. Here, we find that the ablation of autophagy-essential players disrupts EGF-induced endocytic trafficking of EGFR. Cells lacking ATG7 or ATG16L1 exhibit increased levels of phosphatidylinositol-3-phosphate (PI(3)P), a key determinant of early endosome maturation. Increased PI(3)P levels are associated with an accumulation of EEA1-positive endosomes where EGFR trafficking is stalled. Aberrant early endosomes are recognised by the autophagy machinery in a TBK1- and Gal8-dependent manner and are delivered to LAMP2-positive lysosomes. Preventing this homeostatic regulation of early endosomes by autophagy reduces EGFR recycling to the plasma membrane and compromises downstream signalling and cell survival. Our findings uncover a novel role for the autophagy machinery in maintaining early endosome function and growth factor sensing.

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EMBO reports, , 1469-3178, e47734, 2019

PMID: 31448519

Group Members

Latest Publications

An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis.

Odle RI, Walker SA, Oxley D

Molecular cell
1097-4164: (2019)

PMID: 31733992

Autophagosome biogenesis machinery.

Walker SA, Ktistakis NT

Journal of molecular biology
1089-8638: (2019)

PMID: 31705882

Targeting of early endosomes by autophagy facilitates EGFR recycling and signalling.

Fraser J, Simpson J, Fontana R

EMBO reports
1469-3178:e47734 (2019)

PMID: 31448519

Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform.

Zachari M, Gudmundsson SR, Li Z

Developmental cell
1878-1551: (2019)

PMID: 31353311

Autophagy, Inflammation, and Metabolism (AIM) Center in its second year.

Deretic V, Prossnitz E, Burge M

Autophagy
15 1554-8635:1829-1833 (2019)

PMID: 31234750

Who plays the ferryman: ATG2 channels lipids into the forming autophagosome.

Ktistakis NT

The Journal of cell biology
1540-8140: (2019)

PMID: 31076453

ER platforms mediating autophagosome generation.

Ktistakis NT

Biochimica et biophysica acta. Molecular and cell biology of lipids
1879-2618: (2019)

PMID: 30890442

Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation.

Kumar S, Gu Y, Abudu YP

Developmental cell
1878-1551: (2019)

PMID: 30827897