Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.25.1 (
proteasome
)
28,817
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The ubiquitin-
proteasome
system (UPS) and autophagy-lysosomal pathway (ALP) are two major protein degradation pathways in eukaryotic cells. Initially considered as two independent pathways, there is emerging evidence that they can work in concert. As alterations of UPS and ALP function can contribute to neurodegenerative disorders, cancer and cardiac disease, there is great interest in finding targets that modulate these catabolic processes. We undertook an unbiased, total genome high-throughput screen to identify novel effectors that regulate both the UPS and ALP. We generated a stable HEK293 cell line expressing a UPS reporter (Ub
G76V
-mCherry) and an ALP reporter (GFP-LC3) and screened for genes for which knockdown increased both Ub
G76V
-mCherry intensity and GFP-LC3 puncta. With stringent selection, we isolated 80 candidates, including the transcription factor
ZNF418
(ZFP418 in rodents). After screen validation with
Zfp418
overexpression in HEK293 cells, we evaluated
Zfp418
knockdown and overexpression in neonatal rat ventricular myocytes (NRVMs). Endogenous and overexpressed ZFP418 were localized in the nucleus. Subsequent experiments showed that ZFP418 negatively regulates UPS and positively regulates ALP activity in NRVMs. RNA-seq from
Zfp418
knockdown revealed altered gene expression of numerous ubiquitinating and deubiquitinating enzymes, decreased expression of autophagy activators and initiators and increased expression of autophagy inhibitors. We found that ZPF418 activated the promoters of
Dapk2
and
Fyco1
, which are involved in autophagy. RNA-seq from
Zfp418
knockdown also revealed accumulation of several genes involved in cardiac development and/or hypertrophy. In conclusion, our study provides evidence that
ZNF418
activates the ALP, inhibits the UPS and regulates genes associated with cardiomyocyte structure/function.
...
PMID:A high-throughput screening identifies ZNF418 as a novel regulator of the ubiquitin-proteasome system and autophagy-lysosomal pathway. 3324 83
