β-arrestins attenuate p38-mediated endosome to Golgi transport.
Shiga toxin (Stx) is after endocytosis transported via early endosomes to the Golgi apparatus and endoplasmic reticulum. It is then translocated to the cytosol where it exerts its toxic effect. We recently reported that p38 is required for endosome to Golgi transport of Stx. In the present study, we investigated whether β-arrestins are effectors of this pathway. β-arrestin knockdown led to enhanced Stx transport. A similar phenotype was achieved upon p38 activation. We demonstrate that p38 and β-arrestin act on the same pathway. β-arrestin colocalized with internalized Stx and, interestingly, was recruited to endosomes upon p38 activation. After Stx treatment, p38 and β-arrestin formed a transient complex. From these data we propose that β-arrestin negatively regulates Stx transport via an interaction with activated p38 and attenuation of its signalling. Interestingly, also mannose 6-phosphate receptor transport was regulated by p38 and β-arrestin. β-arrestins therefore seem to regulate an endosome to Golgi pathway used by multiple cargo proteins.
Skånland
Sigrid S
SS
Centre for Cancer Biomedicine, Faculty Division Norwegian Radium Hospital, University of Oslo, Oslo, Norway.
Wälchli
Sébastien
S
Sandvig
Kirsten
K
D019390:Arrestins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D004789:Enzyme Activation; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D021381:Protein Transport / Q000502:physiology; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D022621:Shiga Toxin / Q000493:pharmacokinetics*; D000071557:beta-Arrestins; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D019390:Arrestins; D017527:Receptor, IGF Type 2; D000071557:beta-Arrestins; D022621:Shiga Toxin; D048051:p38 Mitogen-Activated Protein Kinases