DNAJC10 (also known as ERdj5) is a member of the DnaJ/Hsp40 family of molecular chaperones. DNAJC10 is primarily localized to the endoplasmic reticulum (ER) where it plays critical roles in protein folding, quality control, and ER-associated degradation (ERAD). This chaperone has emerged as an important player in neurodegenerative diseases characterized by protein misfolding and ER stress.
DNAJC10/ERdj5 possesses multiple domains and functions:
- J Domain: Binds to Hsp70 family proteins and stimulates their ATPase activity
- Client Binding Domain: Recognizes and binds to misfolded proteins
- Thioredoxin Domains: Contains two thioredoxin-like domains with redox activity
- ER Localization: Contains an ER retention signal (KDEL or RDEL)
- ERAD Function: Facilitates retrotranslocation of misfolded proteins for degradation
DNAJC10/ERdj5 functions as a specialized ERAD co-chaperone:
- Substrate recognition: The J domain and client-binding region identify misfolded proteins in the ER lumen
- Hsp70 recruitment: DNAJC10 recruits BiP (GRP78) through J domain-mediated stimulation
- Redox regulation: Thioredoxin domains maintain substrate redox state for proper folding
- Retrotranslocation: Facilitates transfer of substrates to the Derlin channel
- Dislocation: Co-operates with EDEM and PDI for substrate extraction
¶ Protein Domain Structure
| Domain |
Position |
Function |
| J domain |
N-terminal |
Hsp70 ATPase stimulation |
| Client binding |
Central |
Substrate recognition |
| Thioredoxin 1 |
C-terminal |
Redox activity |
| Thioredoxin 2 |
C-terminal |
Dimerization |
- ER Stress Response: DNAJC10 helps manage ER stress induced by Aβ accumulation
- Protein Quality Control: Enhances clearance of misfolded proteins through ERAD
- Calcium Homeostasis: ER chaperone function affects calcium signaling
- Synaptic Protection: May protect synapses from protein aggregation
- α-Synuclein Clearance: DNAJC10 may facilitate clearance of misfolded α-synuclein
- ER Stress: PD-associated proteins induce ER stress that DNAJC10 helps manage
- Dopaminergic Neuron Vulnerability: The unfolded protein response in dopaminergic neurons
- Protein Aggregation: DNAJC10 helps manage aggregation-prone proteins in ALS
- ERAD Enhancement: May enhance clearance of mutant SOD1 and TDP-43
- Motor Neuron Stress: ER stress is a key feature of ALS pathogenesis
Chronic ER stress triggers the unfolded protein response (UPR):
- IRE1 pathway: Pro-apoptotic splicing of XBP1
- PERK pathway: Translation repression, CHOP induction
- ATF6 pathway: Pro-apoptotic gene expression
DNAJC10 deficiency contributes to:
- Impaired clearance of aggregation-prone proteins
- Increased load on proteostasis systems
- Formation of toxic oligomers
ER chaperone dysfunction affects:
- ER calcium store maintenance
- Calcium signaling abnormalities
- Mitochondrial calcium overload
- ERAD Enhancers: Compounds that enhance ERAD function are being explored
- Chaperone Co-inducers: Small molecules that upregulate DNAJC10 expression
- Protein Aggregation Inhibitors: Combination approaches targeting multiple pathways
- Biomarkers: DNAJC10 expression as a marker of ER stress
- Genetic Studies: DNAJC10 polymorphisms and disease risk
- Therapeutic Targeting: Developing modulators of DNAJC10 function
DNAJC10 shows regulated expression:
- Brain Regions: Expressed in cortex, hippocampus, and various brain regions
- Cellular Localization: ER lumen, with some nuclear localization reported
- Stress Induction: Expression is upregulated by ER stress conditions
DNAJC10 interacts with multiple proteins:
- BiP/GRP78: Major ER Hsp70 that cooperates with DNAJC10
- Derlins: Components of the ERAD retrotranslocation channel
- EDEM: ER degradation-enhancing α-mannosidase-like protein
- PDI: Protein disulfide isomerase family members
- SEL1L: ERAD adaptor protein
- OS-9: ERAD lectin for misfolded glycoproteins
DNAJC10 knockout mice show:
- Embryonic lethality (some alleles)
- ER stress accumulation
- Impaired protein quality control
DNAJC10 overexpression provides:
- Enhanced ERAD function
- Protection against proteotoxic stress
- Improved protein clearance
DNAJC10 polymorphisms have been associated with:
- AD risk in some populations
- PD progression
- ALS age of onset
DNAJC10 is a promising therapeutic target:
- Small molecule inducers: Upregulate DNAJC10 expression
- ERAD modulators: Enhance substrate clearance
- Chaperone agonists: Stabilize DNAJC10 function