PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury

Cell Rep. 2017 Jun 20;19(12):2586-2597. doi: 10.1016/j.celrep.2017.05.080.

Abstract

Polarized vesicle transport plays an important role in cell polarization, but the mechanisms underlying this process and its role in innate immune responses are not well understood. Here, we describe a phosphorylation-regulated polarization mechanism that is important for neutrophil adhesion to endothelial cells during inflammatory responses. We show that the protein kinase PKN1 phosphorylates RPH3A, which enhances binding of RPH3A to guanosine triphosphate (GTP)-bound RAB21. These interactions are important for polarized localization of RAB21 and RPH3A in neutrophils, which leads to PIP5K1C90 polarization. Consistent with the roles of PIP5K1C90 polarization, the lack of PKN1 or RPH3A impairs neutrophil integrin activation, adhesion to endothelial cells, and infiltration in inflammatory models. Furthermore, myeloid-specific loss of PKN1 decreases tissue injury in a renal ischemia-reperfusion model. Thus, this study characterizes a mechanism for protein polarization in neutrophils and identifies a potential protein kinase target for therapeutic intervention in reperfusion-related tissue injury.

Keywords: PIP5K1C90; PKN1; RAB21; RPH3A; adhesion; neutrophil polarization; renal ischemia-reperfusion; vesicle trafficking.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Adhesion
  • Cell Polarity
  • Female
  • Kidney / blood supply*
  • Kidney / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism*
  • Neutrophils / physiology*
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Kinase C / physiology*
  • Protein Processing, Post-Translational
  • Protein Transport
  • Reperfusion Injury / enzymology
  • Reperfusion Injury / immunology
  • Reperfusion Injury / pathology
  • Transendothelial and Transepithelial Migration
  • Transport Vesicles / metabolism
  • Vesicular Transport Proteins / metabolism*
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Nerve Tissue Proteins
  • Vesicular Transport Proteins
  • rabphilin-3A
  • Phosphotransferases (Alcohol Group Acceptor)
  • protein kinase N
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • Protein Kinase C
  • rab21 protein, mouse
  • rab GTP-Binding Proteins