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LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes.

Publication ,  Journal Article
Liu, Z; Xu, E; Zhao, HT; Cole, T; West, AB
Published in: EMBO J
October 15, 2020

Genetic variation in LRRK2 associates with the susceptibility to Parkinson's disease, Crohn's disease, and mycobacteria infection. High expression of LRRK2 and its substrate Rab10 occurs in phagocytic cells in the immune system. In mouse and human primary macrophages, dendritic cells, and microglia-like cells, we find that Rab10 specifically regulates a specialized form of endocytosis known as macropinocytosis, without affecting phagocytosis or clathrin-mediated endocytosis. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GTP-Rab10, before EEA1 and Rab5 recruitment to early macropinosomes occurs. Macropinosome cargo in macrophages includes CCR5, CD11b, and MHCII, and LRRK2-phosphorylation of Rab10 potently blocks EHBP1L1-mediated recycling tubules and cargo turnover. EHBP1L1 overexpression competitively inhibits LRRK2-phosphorylation of Rab10, mimicking the effects of LRRK2 kinase inhibition in promoting cargo recycling. Both Rab10 knockdown and LRRK2 kinase inhibition potently suppress the maturation of macropinosome-derived CCR5-loaded signaling endosomes that are critical for CCL5-induced immunological responses that include Akt activation and chemotaxis. These data support a novel signaling axis in the endolysosomal system whereby LRRK2-mediated Rab10 phosphorylation stalls vesicle fast recycling to promote PI3K-Akt immunological responses.

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Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

October 15, 2020

Volume

39

Issue

20

Start / End Page

e104862

Location

England

Related Subject Headings

  • rab GTP-Binding Proteins
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Protein Binding
  • Pinocytosis
  • Phosphorylation
  • Phagocytes
  • Mutation
  • Monocytes
  • Microglia
 

Citation

APA
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ICMJE
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Liu, Z., Xu, E., Zhao, H. T., Cole, T., & West, A. B. (2020). LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes. EMBO J, 39(20), e104862. https://doi.org/10.15252/embj.2020104862
Liu, Zhiyong, Enquan Xu, Hien Tran Zhao, Tracy Cole, and Andrew B. West. “LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes.EMBO J 39, no. 20 (October 15, 2020): e104862. https://doi.org/10.15252/embj.2020104862.
Liu Z, Xu E, Zhao HT, Cole T, West AB. LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes. EMBO J. 2020 Oct 15;39(20):e104862.
Liu, Zhiyong, et al. “LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes.EMBO J, vol. 39, no. 20, Oct. 2020, p. e104862. Pubmed, doi:10.15252/embj.2020104862.
Liu Z, Xu E, Zhao HT, Cole T, West AB. LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes. EMBO J. 2020 Oct 15;39(20):e104862.

Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

October 15, 2020

Volume

39

Issue

20

Start / End Page

e104862

Location

England

Related Subject Headings

  • rab GTP-Binding Proteins
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Protein Binding
  • Pinocytosis
  • Phosphorylation
  • Phagocytes
  • Mutation
  • Monocytes
  • Microglia