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LRRK2 is required for CD38-mediated NAADP-Ca2+ signaling and the downstream activation of TFEB (transcription factor EB) in immune cells.

Authors
  • Nabar, Neel R1
  • Heijjer, Christopher N1
  • Shi, Chong-Shan1
  • Hwang, Il-Young1
  • Ganesan, Sundar2
  • Karlsson, Mikael C I3
  • Kehrl, John H1
  • 1 B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 2 Biological Imaging Section, Research Technologies Branch, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 3 Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
Type
Published Article
Journal
Autophagy
Publisher
Landes Bioscience
Publication Date
Jul 27, 2021
Pages
1–19
Identifiers
DOI: 10.1080/15548627.2021.1954779
PMID: 34313548
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

CD38 is a cell surface receptor capable of generating calcium-mobilizing second messengers. It has been implicated in host defense and cancer biology, but signaling mechanisms downstream of CD38 remain unclear. Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common genetic cause of Parkinson disease; it is also a risk factor for Crohn disease, leprosy, and certain types of cancers. The pathogenesis of these diseases involves inflammation and macroautophagy/autophagy, processes both CD38 and LRRK2 are implicated in. Here, we mechanistically and functionally link CD38 and LRRK2 as upstream activators of TFEB (transcription factor EB), a host defense transcription factor and the master transcriptional regulator of the autophagy/lysosome machinery. In B-lymphocytes and macrophages, we show that CD38 and LRRK2 exist in a complex on the plasma membrane. Ligation of CD38 with the monoclonal antibody clone 90 results in internalization of the CD38-LRRK2 complex and its targeting to the endolysosomal system. This generates an NAADP-dependent calcium signal, which requires LRRK2 kinase activity, and results in the downstream activation of TFEB. lrrk2 KO macrophages accordingly have TFEB activation defects following CD38 or LPS stimulation and fail to switch to glycolytic metabolism after LPS treatment. In overexpression models, the pathogenic LRRK2G2019S mutant promotes hyperactivation of TFEB even in the absence of CD38, both by stabilizing TFEB and promoting its nuclear translocation via aberrant calcium signaling. In sum, we have identified a physiological CD38-LRRK2-TFEB signaling axis in immune cells. The common pathogenic mutant, LRRK2G2019S, appears to hijack this pathway.

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