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Macrophage Migration and Phagocytosis Are Controlled by Kindlin-3's Link to the Cytoskeleton

Huan Liu1, Liang Zhu2, Tejasvi Dudiki1

  • 1Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.

Journal of Immunology (Baltimore, Md. : 1950)
|February 26, 2020
PubMed

Insights

Kindlin-3 normally limits myeloid cell movement and phagocytosis by binding paxillin and leupaxin. Disrupting this interaction unexpectedly enhances these crucial immune functions, revealing a novel regulatory mechanism.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Myeloid cell functions like migration and phagocytosis depend on integrin adhesion complexes (adhesome).
  • Kindlin-3 is essential for these functions, and its deficiency causes severe immunodeficiency.
  • The precise mechanisms of Kindlin-3 incorporation into the adhesome and its regulation remain unclear.

Purpose of the Study:

  • To investigate the interaction between Kindlin-3 and adhesome proteins.
  • To elucidate how Kindlin-3 binding to paxillin (PXN) and leupaxin (LPXN) influences myeloid cell functions.

Main Methods:

  • Nuclear magnetic resonance (NMR) spectroscopy to identify Kindlin-3 interaction sites.
  • Functional assays in Raw 264.7 macrophages to assess cell motility, polarization, and phagocytosis.

Main Results:

  • Kindlin-3 directly binds to paxillin (PXN) and leupaxin (LPXN) via its F0 domain (G43/L47).
  • Disrupting Kindlin-3-PXN/LPXN interactions enhanced macrophage cell spreading, polarization, and motility.
  • Interruption of this binding promoted a shift to amoeboid movement and augmented phagocytic activity.

Conclusions:

  • Novel interactions between Kindlin-3 and PXN/LPXN were identified, revealing a mechanism that limits myeloid cell motility and phagocytosis.
  • These findings uncover a critical immune regulatory pathway involving the adhesome and Kindlin-3.

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