Autophagy is an evolutionarily conserved process that is essential for cellular homeostasis and organismal viability in eukaryotes. However, the extent of its functions in higher-order processes of organismal physiology and behavior is still unknown. Here, we report that autophagy is essential for the maintenance of balance in mice and that its deficiency leads to severe balance disorders. We generated mice deficient in autophagin-1 protease (Atg4b) and showed that they had substantial systemic reduction of autophagic activity. Autophagy reduction occurred through defective proteolytic processing of the autophagosome component LC3 and its paralogs, which compromised the rate of autophagosome maturation. Despite their viability, Atg4b-null mice showed unusual patterns of behavior that are common features of inner ear pathologies. Consistent with this, Atg4b-null mice showed defects in the development of otoconia, organic calcium carbonate crystals essential for sense of balance (equilibrioception). Furthermore, these abnormalities were exacerbated in Atg5–/– mice, which completely lack the ability to perform autophagy, confirming that autophagic activity is necessary for otoconial biogenesis. Autophagy deficiency also led to impaired secretion and assembly of otoconial core proteins, thus hampering otoconial development. Taken together, these results describe an essential role for autophagy in inner ear development and equilibrioception and open new possibilities for understanding and treating human balance disorders, which are of growing relevance among the elderly population.
Guillermo Mariño, Alvaro F. Fernández, Sandra Cabrera, Yunxia W. Lundberg, Rubén Cabanillas, Francisco Rodríguez, Natalia Salvador-Montoliu, José A. Vega, Antonino Germanà, Antonio Fueyo, José M.P. Freije, Carlos López-Otín
Title and authors | Publication | Year |
---|---|---|
A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B
D Bosc, L Vezenkov, S Bortnik, J An, J Xu, C Choutka, AM Hannigan, S Kovacic, S Loo, PG Clark, G Chen, RN Guay-Ross, K Yang, WH Dragowska, F Zhang, NE Go, A Leung, NS Honson, TA Pfeifer, M Gleave, M Bally, SJ Jones, SM Gorski, RN Young |
Scientific Reports | 2018 |
Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo
Y Fu, L Hong, J Xu, G Zhong, Q Gu, Q Gu, Y Guan, X Zheng, Q Dai, X Luo, C Liu, Z Huang, XM Yin, P Liu, M Li |
Autophagy | 2018 |
Targeting the miR-665-3p-ATG4B-autophagy axis relieves inflammation and apoptosis in intestinal ischemia/reperfusion
Z Li, G Wang, D Feng, G Zu, Y Li, X Shi, Y Zhao, H Jing, S Ning, W Le, J Yao, X Tian |
Cell Death and Disease | 2018 |
Delipidation of mammalian Atg8-family proteins by each of the four ATG4 proteases
KJ Kauffman, S Yu, J Jin, B Mugo, N Nguyen, A O'Brien, S Nag, AH Lystad, TJ Melia |
Autophagy | 2018 |
AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells
Z Ni, J He, Y Wu, C Hu, X Dai, X Yan, B Li, X Li, H Xiong, Y Li, S Li, L Xu, Y Li, J Lian, F He |
Autophagy | 2018 |
Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model
J Hirt, K Porter, A Dixon, S McKinnon, PB Liton |
Cell Death Discovery | 2018 |
Autophagy proteins suppress protective type I interferon signalling in response to the murine gut microbiota
PK Martin, A Marchiando, R Xu, E Rudensky, F Yeung, SL Schuster, E Kernbauer, K Cadwell |
Nature Microbiology | 2018 |
Impaired autophagic activity and ATG4B deficiency are associated with increased endoplasmic reticulum stress-induced lung injury
M Maciel, D Hernández-Barrientos, I Herrera, M Selman, A Pardo, S Cabrera |
Aging | 2018 |
ER‐to‐lysosome‐associated degradation of proteasome‐resistant ATZ polymers occurs via receptor‐mediated vesicular transport
I Fregno, E Fasana, TJ Bergmann, A Raimondi, M Loi, T Soldà, C Galli, R D'Antuono, D Morone, A Danieli, P Paganetti, E van Anken, M Molinari |
The EMBO Journal | 2018 |
Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy.
Liu PF, Tsai KL, Hsu CJ, Tsai WL, Cheng JS, Chang HW, Shiau CW, Goan YG, Tseng HH, Wu CH, Reed JC, Yang LW, Shu CW |
Theranostics | 2018 |