Mitochondria mediate septin cage assembly to promote autophagy of Shigella

Abstract

Septins, cytoskeletal proteins with well‐characterised roles in cytokinesis, form cage‐like structures around cytosolic Shigella flexneri and promote their targeting to autophagosomes. However, the processes underlying septin cage assembly, and whether they influence S. flexneri proliferation, remain to be established. Using single‐cell analysis, we show that the septin cages inhibit S. flexneri proliferation. To study mechanisms of septin cage assembly, we used proteomics and found mitochondrial proteins associate with septins in S. flexneri‐infected cells. Strikingly, mitochondria associated with S. flexneri promote septin assembly into cages that entrap bacteria for autophagy. We demonstrate that the cytosolic GTPase dynamin‐related protein 1 (Drp1) interacts with septins to enhance mitochondrial fission. To avoid autophagy, actin‐polymerising Shigella fragment mitochondria to escape from septin caging. Our results demonstrate a role for mitochondria in anti‐Shigella autophagy and uncover a fundamental link between septin assembly and mitochondria.

Septins and Bacterial Infection

“…Indeed, the frequency of actin tails is significantly enhanced in septin-depleted cells infected with bacteria normally recognized by septin cages. Recent work has also shown that septin cages assemble to restrict bacterial replication (Sirianni et al, 2016). Septin cages have been observed for both S. flexneri and M. marinum during infection of tissue culture cells in vitro and during infection of zebrafish in vivo (Mostowy et al, 2010, 2013; Sirianni et al, 2016).…”

Cancer-Related Functions and Subcellular Localizations of Septins

“…SEPT2 and 7, by interacting with DRP1 would concentrate it at the sites of mitochondrial constriction and facilitate their fission (Pagliuso et al, 2016; Sirianni et al, 2016). Mitochondria-associated septins also comprise the isoform 2 of SEPT4 (SEPT4_i2) also called ARTS, which upon pro-apoptotic stimuli, is released in the cytosol where it binds to the XIAP proteins to release the inhibition of caspases and thus promote apoptosis (Edison et al, 2012).…”

Septins As Modulators of Endo-Lysosomal Membrane Traffic

“…Interestingly, it has been noted that SEPT9 and SEPT7 are incorporated into septin cages that entrap cytosolic Shigella to target them for autophagy (Mostowy et al, 2010; Sirianni et al, 2016; Figure 1H). Septin cage formation occurs in concert with, and dependent on proteins involved in autophagy, including p62/SQSTM1, Atg5, Atg6, and Atg7.…”