Abstract
Recessive mutations in DNAJC3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation.
Highlights
DnaJ Heat Shock Protein Family (Hsp40) Member C3 (DNAJC3, p58IPK ) is an endoplasmic reticulum (ER)-resident co-chaperone of BiP (GRP78, HSPA5), which transiently binds to a broad range of newly synthesized proteins present in the ER to impede the misfolding of susceptible domains
The most significantly downregulated protein was DnaJ heat shock protein family member C3 (DNAJC3), which was expressed at log2−2.66 in DNAJC3mut fibroblasts compared to controls, confirming that the mutations lead to reduced protein level and demonstrating the robustness of our untargeted proteomic profiling approach
Bi-allelic loss-of-function mutations in DNAJC3, encoding a co-chaperone of BiP, one of the major chaperones of the ER, have been shown to cause neurodegeneration with early-onset ataxia, upper-motor-neuron signs, demyelinating neuropathy, and cerebral atrophy associated with diabetes mellitus (Synofzik et al, 2014)
Summary
DnaJ Heat Shock Protein Family (Hsp40) Member C3 (DNAJC3, p58IPK ) is an endoplasmic reticulum (ER)-resident co-chaperone of BiP (GRP78, HSPA5), which transiently binds to a broad range of newly synthesized proteins present in the ER to impede the misfolding of susceptible domains. Activated DNAJC3 is thought to downregulate the signaling of the unfolded protein response (UPR) effector PERK [protein kinase R (PKR)-like endoplasmic reticulum kinase], presumably by interaction with its cytoplasmic domain (Yan et al, 2002). Inhibition of PERK dimerization by DNAJC3 increases protein synthesis and, during periods of sustained UPR signaling, assists in returning the ER to normal homeostasis. Dysregulation of this process may have toxic effects on cellular protein homeostasis. DNAJC3 affects ER maintenance and apoptosis, under conditions of cellular stress, and it has been highlighted as a protective factor in retinal neurons (Boriushkin et al, 2015)
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