- PIKfyve inhibition elevates PI3P and induces LRRK2 hyperactivation; concurrent inhibition of class III PI3K that generates PI3P suppresses this activation.
- LRRK2 hyperactivation requires CASM and Rab activity; CASM inhibition or Rab12/Rab29 loss prevents PIKfyve inhibitor-induced LRRK2 activation.
- LRRK2 binds PI3P directly via N-terminal basic residues and colocalises with phospho-Rab10 on LAMP1-positive enlarged vacuoles.
Life Sci Alliance. 2026 Nov 6;10(1):e202603939. doi: 10.26508/lsa.202603939. Print 2027 Jan.
ABSTRACT
LRRK2 is a Parkinson’s disease-associated kinase that phosphorylates Rab GTPases. Hyperactivation of LRRK2, which is thought to cause Parkinson’s disease, occurs on stressed endolysosomal membranes via conjugation of ATG8 to single membranes (CASM) and Rab, whereas the involvement of specific membrane lipids remained unclear. Here, we found that the inhibition of PIKfyve that metabolizes phosphatidylinositol 3-phosphate (PI3P) induces hyperactivation of LRRK2 and that additional inhibition of the class III phosphoinositide 3-kinase that generates PI3P suppressed LRRK2 hyperactivation. Cellular PI3P levels were indeed elevated when LRRK2 was activated. CASM-induced activation of LRRK2, but not CASM itself, was suppressed by phosphoinositide 3-kinase inhibitors, whereas inhibition of CASM or Rab12/Rab29 suppressed LRRK2 activation induced by PIKfyve inhibitors. LRRK2 and phospho-Rab10 were colocalized with PI3P on LAMP1-positive enlarged vacuoles, and LRRK2 directly bound PI3P in vitro via its N-terminal positively charged amino acids. Together, we propose an updated mechanism of LRRK2 hyperactivation that simultaneously requires CASM, Rab, and PI3P-rich membranes.
PMID:42994990 | DOI:10.26508/lsa.202603939
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