CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity.
Autophagy
; : 1-11, 2024 Jul 30.
Article
in En
| MEDLINE
| ID: mdl-38869076
ABSTRACT
Protein aggregation caused by the disruption of proteostasis will lead to cellular cytotoxicity and even cell death, which is implicated in multiple neurodegenerative diseases. The elimination of aggregated proteins is mediated by selective macroautophagy receptors, which is termed aggrephagy. However, the identity and redundancy of aggrephagy receptors in recognizing substrates remain largely unexplored. Here, we find that CCDC50, a highly expressed autophagy receptor in brain, is recruited to proteotoxic stresses-induced polyubiquitinated protein aggregates and ectopically expressed aggregation-prone proteins. CCDC50 recognizes and further clears these cytotoxic aggregates through autophagy. The ectopic expression of CCDC50 increases the tolerance to stress-induced proteotoxicity and hence improved cell survival in neuron cells, whereas CCDC50 deficiency caused accumulation of lipid deposits and polyubiquitinated protein conjugates in the brain of one-year-old mice. Our study illustrates how aggrephagy receptor CCDC50 combats proteotoxic stress for the benefit of neuronal cell survival, thus suggesting a protective role in neurotoxic proteinopathy.Abbreviations AD Alzheimer disease; ALS amyotrophic lateral sclerosis; ATG5 autophagy related 5; BODIPY boron-dipyrromethene; CASP3 caspase 3; CCDC50 coiled-coil domain containing 50; CCT2 chaperonin containing TCP1 subunit 2; CHX cycloheximide; CQ chloroquine; CRISPR clustered regulatory interspaced short palindromic repeat; Cas9 CRISPR-associated system 9; DAPI 4',6-diamidino-2-phenylindole; FK2 Anti-ubiquitinylated proteins antibody, clone FK2; FUS FUS RNA binding protein; GFP green fluorescent protein; HD Huntington disease; HTT huntingtin; KEGG Kyoto Encyclopedia of Genes and Genomes; LDS LIR-docking site; LIR LC3-interacting region; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MAPT/tau microtubule associated protein tau; MIU motif interacting with ubiquitin; NBR1 NBR1, autophagy cargo receptor; OPTN optineurin; PD Parkinson disease; PI propidium iodide; ROS reactive oxygen species; SOD1 superoxide dismutase 1; SQSTM1/p62 sequestosome 1; TAX1BP1 Tax1 binding protein 1; Ub ubiquitin; UDS UIM-docking site; UIM ubiquitin interacting motif; UPS ubiquitin-proteasome system.
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MEDLINE
Language:
En
Journal:
Autophagy
Year:
2024
Document type:
Article