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LRRK 2 regulates endoplasmic reticulum–mitochondrial tethering through the PERK ‐mediated ubiquitination pathway
Author(s) -
Toyofuku Toshihiko,
Okamoto Yuki,
Ishikawa Takako,
Sasawatari Shigemi,
Kumanogoh Atsushi
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100875
Subject(s) - endoplasmic reticulum , microbiology and biotechnology , parkin , ubiquitin , phosphorylation , unfolded protein response , kinase , mitochondrion , biology , tethering , lrrk2 , biochemistry , mutation , medicine , gene , disease , pathology , parkinson's disease
Mutations in the leucine‐rich repeat kinase 2 ( LRRK 2 ) gene are the most common cause of familial Parkinson's disease ( PD ). Impaired mitochondrial function is suspected to play a major role in PD . Nonetheless, the underlying mechanism by which impaired LRRK 2 activity contributes to PD pathology remains unclear. Here, we identified the role of LRRK 2 in endoplasmic reticulum ( ER )–mitochondrial tethering, which is essential for mitochondrial bioenergetics. LRRK 2 regulated the activities of E3 ubiquitin ligases MARCH 5, MULAN , and Parkin via kinase‐dependent protein–protein interactions. Kinase‐active LRRK 2(G2019S) dissociated from these ligases, leading to their PERK ‐mediated phosphorylation and activation, thereby increasing ubiquitin‐mediated degradation of ER –mitochondrial tethering proteins. By contrast, kinase‐dead LRRK 2(D1994A)‐bound ligases blocked PERK ‐mediated phosphorylation and activation of E3 ligases, thereby increasing the levels of ER –mitochondrial tethering proteins. Thus, the role of LRRK 2 in the ER –mitochondrial interaction represents an important control point for cell fate and pathogenesis in PD .