Rab12 Localizes to Shiga Toxin‐Induced Plasma Membrane Invaginations and Controls Toxin Transport

Rydell, Gustaf E.; Renard, Henri-François; Garcia-Castillo, Maria-Daniela; Dingli, Florent; Loew, Damarys; Lamaze, Christophe; Römer, Winfried; Johannes, Ludger

doi:10.1111/tra.12173

Cited by 15 publications

(8 citation statements)

References 41 publications

(71 reference statements)

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“…Rab12 has been reported to be involved in transferrin receptor trafficking from recycling endosomes to lysosomes [26] and in retrograde trafficking of Shiga toxin [29]. Given that transferrin receptor can be localized to ULK-positive autophagosomes under amino acid starvation [28] and that Shiga toxin can induce autophagy and localize to autophagosomes [30], our data suggest the role of Rab12 in autophagosome trafficking accounts for the phenomena of the involvement of Rab12 in transferrin receptor and Shiga toxin transport.…”

Section: Dennd3 and Rab12 Mediate Autophagosome Traffickingmentioning

confidence: 58%

Phosphorylation of the exchange factor DENND 3 by ULK in response to starvation activates Rab12 and induces autophagy

Fotouhi

McPherson

2015

EMBO Reports

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Unc-51-like kinases (ULKs) are the most upstream kinases in the initiation of autophagy, yet the molecular mechanisms underlying their function are poorly understood. We report a new role for ULK in the induction of autophagy. ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. Through binding to LC3 and associating with LC3-positive autophagosomes, active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy.

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Section: Dennd3 and Rab12 Mediate Autophagosome Traffickingmentioning

confidence: 58%

Phosphorylation of the exchange factor DENND 3 by ULK in response to starvation activates Rab12 and induces autophagy

Fotouhi

McPherson

2015

EMBO Reports

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“…Shiga toxin has been shown to induce plasma membrane invaginations involved in its uptake into cells [48][49][50][51][52]. In a recent paper, Renard and coworkers [48] demonstrate that endophilin A2 is recruited to sites of StxB (and CtxB) internalization, functioning in membrane scission.…”

Section: Discussionmentioning

confidence: 99%

Cross-linking of glycosphingolipids at the plasma membrane: consequences for intracellular signaling and traffic

Klokk

Kavaliauskiene

Sandvig

2015

Cell. Mol. Life Sci.

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Glycosphingolipids (GSLs) are predominantly found in the outer leaflet of the plasma membrane, where they play a role in important processes such as cell adhesion, migration and signaling. However, by which mechanisms GSLs regulate these processes remains elusive. In this study, we therefore took advantage of the fact that some GSLs also serve as receptors for certain protein toxins, which rely on receptor binding for internalization and intoxication. Here, we demonstrate that Shiga and cholera toxins, which both possess multivalent GSL-binding capacity, induce dissociation of the cytosolic cPLA2α-AnxA1 complex in HeLa and HMEC-1 cells. The dissociation is mediated through an increase in cytosolic calcium levels and activation of the tyrosine kinase Syk. Ricin, a protein toxin that does not cross-link surface molecules, has no effect on the same complex. Importantly, we find that antibody-mediated cross-linking of Gb3 and GM1, the GSL receptors for Shiga and cholera toxin, respectively, also induces dissociation. These data demonstrate that cross-linking of GSLs at the plasma membrane mediates the intracellular signaling events resulting in dissociation of the complex. After dissociation, cPLA2α and AnxA1 are translocated to intracellular membranes where they are known to function in regulating membrane transport processes. In conclusion, we have characterized a novel mechanism for cell surface-induced initiation of intracellular signaling and transport events.

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“…A number of cytosolic proteins have been shown to functionally associate with these invaginations (Renard et al, 2015;Römer et al, 2007Römer et al, , 2010Rydell et al, 2014). Here, we identified the first cellular transmembrane machinery, the v-SNAREs VAMP2, VAMP3 and VAMP8, to localize to Shiga-toxininduced plasma membrane invaginations and very early endocytic carriers, to be required for efficient retrograde toxin transport to the Golgi complex, and to be necessary for cell intoxication.…”

Section: Discussionmentioning

confidence: 67%

Shiga toxin stimulates clathrin-independent endocytosis of VAMP2/3/8 SNARE proteins

Renard

García-Castillo

Chambon

et al. 2015

Journal of Cell Science

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Endocytosis is an essential cellular process that is often hijacked by pathogens and pathogenic products. Endocytic processes can be classified into two broad categories, those that are dependent on clathrin and those that are not. The SNARE proteins VAMP2, VAMP3 and VAMP8 are internalized in a clathrin-dependent manner. However, the full scope of their endocytic behavior has not yet been elucidated. Here, we found that VAMP2, VAMP3 and VAMP8 are localized on plasma membrane invaginations and very early uptake structures that are induced by the bacterial Shiga toxin, which enters cells by clathrin-independent endocytosis. We show that toxin trafficking into cells and cell intoxication rely on these SNARE proteins. Of note, the cellular uptake of VAMP3 is increased in the presence of Shiga toxin, even when clathrin-dependent endocytosis is blocked. We therefore conclude that VAMP2, VAMP3 and VAMP8 are removed from the plasma membrane by non-clathrin-mediated pathways, in addition to by clathrin-dependent uptake. Moreover, our study identifies these SNARE proteins as the first transmembrane trafficking factors that functionally associate at the plasma membrane with the toxin-driven clathrin-independent invaginations during the uptake process.

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Rab12 Localizes to Shiga Toxin‐Induced Plasma Membrane Invaginations and Controls Toxin Transport

Cited by 15 publications

References 41 publications

Phosphorylation of the exchange factor DENND 3 by ULK in response to starvation activates Rab12 and induces autophagy

Phosphorylation of the exchange factor DENND 3 by ULK in response to starvation activates Rab12 and induces autophagy

Cross-linking of glycosphingolipids at the plasma membrane: consequences for intracellular signaling and traffic

Shiga toxin stimulates clathrin-independent endocytosis of VAMP2/3/8 SNARE proteins

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