Autophagy is a highly conserved intracellular degradation process crucial for
cell-autonomous immunity against bacterial infection. However, some bacteria
may subvert the host cytoskeleton to escape recognition from autophagy. In
the cytosol, Shigella flexneri and Listeria monocytogenes use actin-based
motility to avoid cell-autonomous immunity and spread from cell-to-cell.
The host cytoskeleton plays a key role in autophagy and its ability to restrict or
promote bacterial replication. Septins, a cytoskeletal component that interacts
with cellular membranes and actin filaments, are GTP-binding proteins that
polymerize into non-polar filaments and rings. Our lab has discovered that
septin cage-like structures entrap actin-polymerising Shigella targeted to
autophagy. The septin cage is recognized as a mechanism of host defence
mechanism, however the precise fate of septin cage entrapped Shigella
remains unknown.
Evidence has suggested that mitochondria provide membrane for the
biogenesis of autophagosomes during starvation. The role of the mitochondria
during the autophagy of Shigella is unknown. Mitochondria are highly dynamic
organelles characterised by events of membrane fission and fusion. Work has
previously established a role for the host cell division machinery, i.e. actin and
myosin, in the regulation of mitochondrial dynamics (a process called ‘mitokinesis’). Whether septins are also involved in mitochondrial dynamics has not yet been tested. For my thesis, the entrapment of Shigella by septin cages was used as a paradigm to better understand host defence against bacterial infection and to discover new septin biology. Results have shown that mitochondria mediate the assembly of septins into cage that target Shigella to degradation by autophagy. We have also discovered that septins regulate mitochondrial fission. Finally, we have revealed a new link between septins, autophagy, and host cell metabolism. Together these results suggest that a more complete understanding of septin biology during bacterial infection can enable its manipulation for therapeutic purposes.Open Acces
