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Explore a selection of research case studies from the past five years.

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Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.

Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

Autophagy in cells

Maintaining healthy lysosomes

When lysosomes—the cell’s recycling centres—get damaged, several defence systems are activated to prevent cell death. One important repair process involves close contact between the lysosome and the endoplasmic reticulum. This process uses certain proteins and lipids, including PI4K2A, but how PI4K2A reaches damaged lysosomes was unknown. Researchers at the Crick found that vesicles containing the ATG9A protein are responsible for delivering PI4K2A to damaged lysosomes during injury or bacterial infection. Another protein, ARFIP2, also found in the ATG9A vesicles, helps control lipid levels on lysosomes and aids in recycling the vesicles, keeping lysosomes healthy after damage or infection.

ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair

Published in Developmental Cell

Published

Fluorescent image of cells undergoing autophagy

Key molecular events in autophagy outlined

Autophagy - a way of degrading parts of the cell - is a lysosome-mediated process activated by cellular stress which is important for human health. Toxic cytoplasmic material or infectious microbes engulfed in a compartment with two membranes called an autophagosome are delivered to lysosomes for degradation. Autophagosome formation involves a set of specific autophagy proteins, tightly coordinated to orchestrate the formation of this double membrane vesicle. Researchers at the Crick found that the binding protein WIP12b activates the enzyme ULK1, which initiates autophagy. The team found that two key phosphorylation events regulate WIP12b's function and association with the forming autophagosome. These findings shed light on the regulation of this essential process.

WIPI2b recruitment to phagophores and ATG16L1 binding are regulated by ULK1 phosphorylation

Published in EMBO Reports

Published

Structure of V1H

Researchers discover how cells raise the alarm when damaged or infected

Our cells need acidic compartments for digestion and recycling of nutrients. Acid is pumped in by a complex assembly of proteins called the V-ATPase. But what happens when our cells get damaged? The acid leaks out and the cell has to respond. Researchers at the Crick discovered how the V-ATPase proton pump itself sounds the alarm: one protein in the complex recruits a crucial part of the self-eating (autophagy) machinery. They think this is especially important during infection since some bacteria target this pathway, and many viruses like influenza trigger it.

The V-ATPase/ATG16L1 axis is controlled by the V1H subunit

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Published in Molecular Cell

Published

Autophagy in cells

Biogenesis of a waste disposal unit

Autophagosomes—the waste disposal units of the cell—are formed by a process whereby a cup-shaped membrane structure closes around a part of the cytoplasm or a particular cargo. Autophagosome biogenesis is catalysed by the autophagy-related (ATG) proteins but how this works is unclear. Sharon Tooze and collaborators have used machine learning analysis, molecular dynamics simulations and live cell imaging to explore the function of the ATG3 protein. They find that ATG3 contains special structures called amphipathic α helices (AH) that help it associate with membranes, leading to the membrane remodeling required for the formation of autophagosomes. Intriguingly, AH structures are present in other ATG proteins and may have similar functions.

Unique amphipathic α helix drives membrane insertion and enzymatic activity of ATG3

Published in Science advances

Published

Making an autophagosome grow

Autophagy has an important role in cancer and neurodegeneration, and also in processes such as ageing. The ATG9A and ATG2A proteins are essential core members of the autophagosome, the cellular waste disposal unit required for cleanup and recycling of debris such as damaged organelles or proteins. Work from other labs had demonstrated that ATG9A and ATG2A interact, but not how. Now, by integrating data from peptide arrays, crosslinking, and hydrogen-deuterium exchange mass spectrometry together with cryoelectron microscopy, Crick collaborators led by Sharon Tooze’s lab have proposed a molecular model of the ATG9A-2A complex that allows prediction of how the two proteins work together to facilitate autophagosome growth. Mutational analyses targeting the binding interfaces combined with functional activity assays demonstrated the importance of ATG9A-2A complex formation and activity for the creation of autophagosomes. This work sheds light on a vital biological process, and opens the way for further detailed studies.

ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation

Published in Molecular Cell

Published

ATG9A shapes the forming autophagosome through Arfaptin 2 and phosphatidylinositol 4-kinase IIIβ

This paper represents an important step forward in our understanding of ATG9, the only multi-spanning autophagy protein and a major focus of my lab’s current work. Here we discovered the composition of the ATG9 vesicle and uncovered an important role for a protein which can induce membrane curvature and a lipid kinase. I chose this work as it has provided us with important insights into the function of ATG9A.

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Published in Journal of Cell Biology

Published

Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins

This paper follows on from our work on WAC and the role of centrosomes in autophagy. We discovered an important centriolar protein has a specific motif (LIR motif) enabling its binding to a key autophagy protein. In collaborative work, we determined the structure and the important features of the LIR motif, and extended the findings to a group of autophagy proteins to provide an important advance on our understanding of selective autophagy. I chose this work because it is a tour de force of structure and biochemistry and a very substantial collaboration between Structural Biology and Peptide Chemistry STPs

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Published in Nature Communications

Published

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Research case studies 

Explore a selection of recent case studies that spotlight particular areas of research at the Crick.