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Oxidative stress-induced phosphorylation of JIP4 regulates lysosomal positioning in coordination with TRPML1 and ALG2

Lookup NU author(s): Dr Tetsushi Kataura, Dr Viktor Korolchuk



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


©2022 The Authors. Published under the terms of the CC BY 4.0 license.Retrograde transport of lysosomes is recognised as a critical autophagy regulator. Here, we found that acrolein, an aldehyde that is significantly elevated in Parkinson's disease patient serum, enhances autophagy by promoting lysosomal clustering around the microtubule organising centre via a newly identified JIP4-TRPML1-ALG2 pathway. Phosphorylation of JIP4 at T217 by CaMK2G in response to Ca2+ fluxes tightly regulated this system. Increased vulnerability of JIP4 KO cells to acrolein indicated that lysosomal clustering and subsequent autophagy activation served as defence mechanisms against cytotoxicity of acrolein itself. Furthermore, the JIP4-TRPML1-ALG2 pathway was also activated by H2O2, indicating that this system acts as a broad mechanism of the oxidative stress response. Conversely, starvation-induced lysosomal retrograde transport involved both the TMEM55B-JIP4 and TRPML1-ALG2 pathways in the absence of the JIP4 phosphorylation. Therefore, the phosphorylation status of JIP4 acts as a switch that controls the signalling pathways of lysosoma l distribution depending on the type of autophagy-inducing signal.

Publication metadata

Author(s): Sasazawa Y, Souma S, Furuya N, Miura Y, Kazuno S, Kakuta S, Suzuki A, Hashimoto R, Hirawake-Mogi H, Date Y, Imoto M, Ueno T, Kataura T, Korolchuk VI, Tsunemi T, Hattori N, Saiki S

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2022

Volume: 41

Issue: 22

Print publication date: 17/11/2022

Online publication date: 11/10/2022

Acceptance date: 21/09/2022

Date deposited: 25/10/2022

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: John Wiley and Sons Inc


DOI: 10.15252/embj.2022111476


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Funder referenceFunder name
Ministy of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI Grant Number 20H05340,
Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 18K15464, 21K07425, 18KK0242, 18KT0027 and 22H02986
Naito Foundation