Dr. David McEwan
Understanding the Cross-Talk Between Autophagy, Infection & Immunity Pathways
Our Body has developed many cell autonomous mechanisms for dealing with infection. One such defence mechanism is the process of autophagy (Greek meaning “Self-eating”). The process of autophagy involves the formation of a double-membraned autophagosome that captures material and delivers it for degradation in the lysosome (Figure 1).
Figure 1. Autophagosome starts as a pre-autophagomal structure (1) and matures into a phagophore (2) before forming a sealed double membrane autophagosome (3). This in turn can fuse multi-vesicular bodies of the endocytic pathway (4) to form an amphisome (5). The amiphsome then fuses with the lysosome (6) to form an autolysosome (7) where the sequestered material is degraded.
Autophagy is therefore responsible for degrading large intracellular structures that are not easily accessible by the proteasome. For example, autophagy can sequester and deliver damaged mitochondria (Mitophagy), ER (ERpahgy), peroxisomes (Pexophagy), protein aggregates (Aggrephagy) and intracellular pathogens (Xenophagy) (Figure 2). This allows the cell to remove potentially harful structures and also provides a source of recycled material, such as amino acids and lipids, that can be utilised during periods of starvation. In addition, this route of degradation also provides valuable antigens for presentation on the cell surface, thereby activating the adaptive immune response.
Figure 2. Cells treated with Bafilomycin A1 lysosomal inhibitor) to induce accumulation of non-degraded material
AP -Autophagosome; M - Mitochondria
Selectivity during autophagy is obtained through specialist Receptors such as p62/SQSTM1, NBR1, Nix/BNIP3L and OPTN that help recruit autophagy membranes to cargo that is to be degraded in the lysosome (Figure 3).
Adaptors help link cellular machineries, such as fusion and transport proteins complexes, to autophagosomes through interactions on the cytosolic facing surface of the AP (Figure 3).
Figure 3. A depiction of a double membrane autophagosome with mATG8 (LC3/GABARAP) proteins conjugated to phosphatidylethanolamine (PE) on both the inner and outer membranes. mATG8 protein on the autophagosomal lumen interact with autophagy receptor proteins which link directly to cargo to be degraded. mATG8-PE on the cytosolic facing membrane can interact with adaptor proteins that help link the autophagosome to the fusion.
Our lab is focused on understanding how the autophagy pathway interacts with the endocytic pathway and in particular how intracellular pathogens, such as Salmonella, can interact with and manipulate this process to avoid detection and destruction.
McEwan, D. G., Richter, B., Claudi, B., Wigge, C., Wild, P., Farhan, H., McGourty, K., Coxon, F. P., Franz-Wachtel, M., Perdu, B., Akutsu, M., Habermann, A., Kirchof, A., Helfrich, M. H., Odgren, P. R., Van Hul, W., Frangakis, A. S., Rajalingam, K., Macek, B., Holden, D. W., Bumann, D. and Dikic, I. (2015) PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection. Cell host & microbe. 17, 58-71
McEwan, D. G., Popovic, D., Gubas, A., Terawaki, S., Suzuki, H., Stadel, D., Coxon, F. P., Miranda de Stegmann, D., Bhogaraju, S., Maddi, K., Kirchof, A., Gatti, E., Helfrich, M. H., Wakatsuki, S., Behrends, C., Pierre, P. and Dikic, I. (2015) PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Molecular cell. 57, 39-54
McEwan, D. G. and Dikic, I. (2015) PLEKHM1: Adapting to life at the lysosome. Autophagy. 11, 720-722
Sandilands, E., Serrels, B., McEwan, D. G., Morton, J. P., Macagno, J. P., McLeod, K., Stevens, C., Brunton, V. G., Langdon, W. Y., Vidal, M., Sansom, O. J., Dikic, I., Wilkinson, S. and Frame, M. C. (2012) Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling. Nature cell biology. 14, 51-60
Wild, P., Farhan, H., McEwan, D. G., Wagner, S., Rogov, V. V., Brady, N. R., Richter, B., Korac, J., Waidmann, O., Choudhary, C., Dotsch, V., Bumann, D. and Dikic, I. (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science. 333, 228-233
McEwan, D. G. and Dikic, I. (2011) The Three Musketeers of Autophagy: phosphorylation, ubiquitylation and acetylation. Trends in cell biology. 21, 195-201
Novak, I., Kirkin, V., McEwan, D. G., Zhang, J., Wild, P., Rozenknop, A., Rogov, V., Lohr, F., Popovic, D., Occhipinti, A., Reichert, A. S., Terzic, J., Dotsch, V., Ney, P. A. and Dikic, I. (2010) Nix is a selective autophagy receptor for mitochondrial clearance. EMBO reports. 11, 45-51
Kirkin, V., Lamark, T., Sou, Y. S., Bjorkoy, G., Nunn, J. L., Bruun, J. A., Shvets, E., McEwan, D. G., Clausen, T. H., Wild, P., Bilusic, I., Theurillat, J. P., Overvatn, A., Ishii, T., Elazar, Z., Komatsu, M., Dikic, I. and Johansen, T. (2009) A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Molecular cell. 33, 505-516
Sandilands, E., Akbarzadeh, S., Vecchione, A., McEwan, D. G., Frame, M. C. and Heath, J. K. (2007) Src kinase modulates the activation, transport and signalling dynamics of fibroblast growth factor receptors. EMBO reports. 8, 1162-1169
McEwan, D. G., Brunton, V. G., Baillie, G. S., Leslie, N. R., Houslay, M. D. and Frame, M. C. (2007) Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4-regulated compartment via effects on phosphoinositide 3-kinase. Cancer research. 67, 5248-5257