Welcome to the new webpage of the McEwan Lab located in the Welcome Trust building of the School of Life Sciences, University of Dundee, Dundee UK.

My lab is focused on understanding how the autophagy pathway interacts with the endocytic pathway and in particular how intracellular pathogens, such as Salmonella, can manipulate this process to avoid detection and destruction.

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

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.

Figure 2Autophagy 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).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, trafficking and AP formation machinery.