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  current news   Press   selected story    
     
  20 June 2017  
 
Yersinia effector protein (YopO)-mediated phosphorylation of host gelsolin causes calcium-independent activation leading to disruption of actin dynamics
 
 




Authors
Pavithra Singaravelu‡,‖12, Wei Lin Lee‡134, Sheena Wee‡3, Umesh Ghoshdastider‡3, Ke Ding‡3, Jayantha Gunaratne‡3, Jonathan M. Grimes‡,§,¶, Kunchithapadam Swaminathan‖25 and Robert C. Robinson‡3

Author Affiliations
 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research),   Singapore 138673,
§ Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford,   Roosevelt Drive, Oxford OX3 7BN, United Kingdom,
 Diamond Light Source Ltd., Diamond House, Harwell Science & Innovation Campus, Didcot, Oxfordshire   SOX11 0DE, United Kingdom, and
Department of Biological Sciences, National University of Singapore, Singapore 117543

1 Both authors contributed equally to this work.
2 Supported by National University of Singapore.
3 Supported by A*STAR.
4 To whom correspondence may be addressed: Singapore -MIT Alliance for Research and Technology,   Singapore. E-mail: weilin@smart.mit.edu.
5 To whom correspondence may be addressed: Dept. of Biological Sciences, National University of   Singapore, Singapore 117543. E-mail: dbsks@nus.edu.sg.

Published in the Journal of Biological Chemistry on May 12, 2017.

Please click here for the PDF file.
Read profiles of first authors Pavithra Singaravelu and Wei Lin Lee.
Read a highlight of this paper by Shoichiro Ono.

Abstract

Pathogenic Yersinia bacteria cause a range of human diseases. To modulate and evade host immune systems, these yersiniae inject effector proteins into host macrophages. One such protein, the serine/threonine kinase YopO (YpkA in Yersinia pestis), uses monomeric actin as bait to recruit and phosphorylate host actin polymerization - regulating proteins, including the actin-severing protein gelsolin, in order to disrupt actin filaments and thus impair phagocytosis. However, the YopO phosphorylation sites on gelsolin and the consequences of YopO-mediated phosphorylation on actin remodeling have yet to be established. Here we determined the effects of YopO-mediated phosphorylation on gelsolin and identified its phosphorylation sites by mass spectrometry. YopO phosphorylated gelsolin in the linker region between gelsolin homology domains G3 and G4, which in the absence of calcium, are compacted, but adopt an open conformation in the presence of calcium, enabling actin binding and severing. Using phosphomimetic and phosphodeletion gelsolin mutants, we found that YopO-mediated phosphorylation partially mimics calcium-dependent activation of gelsolin, potentially contributing to a reduction in filamentous actin and altered actin dynamics in phagocytic cells. In summary, this work represents the first report of the functional outcome of serine/threonine phosphorylation in gelsolin regulation and provides critical insight into how YopO disrupts normal gelsolin function to alter host actin dynamics and thus cripple phagocytosis.

Figure

Figure legend
: Model for the implications of phosphorylation by YopO on native gelsolin regulation.


For more information on Robert ROBINSON's lab, please click here.