Phosphorylated ubiquitin: a new shade of PINK1 in Parkin activation

Sauvé, Véronique; Gehring, Kalle

doi:10.1038/cr.2014.79

Cited by 11 publications

(8 citation statements)

References 12 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, several other E3 ligases, including CHIP, which is an E3 ubiquitin ligase, were reported to regulate Runx2 protein turnover. CHIP has been reported to directly interact with Runx2 and to induce the ubiquitin‐dependent degradation of the Runx2 protein . These findings indicate that CHIP‐mediated protein degradation plays a role in osteoblast differentiation.…”

Section: Discussionmentioning

confidence: 90%

Identification of C‐terminal Hsp70‐interacting protein as a mediator of tumour necrosis factor action in osteoblast differentiation by targeting osterix for degradation

Xie

2015

J Cellular Molecular Medi

View full text Add to dashboard Cite

In patients with inflammatory arthritis, tumour necrosis factor (TNF)-α are overproduced in inflamed joints. This leads to local erosion of cartilage and bone, periarticular osteopenia, as well as osteoporosis. But less is known regarding the molecular mechanisms that mediate the effect of TNF-α on osteoblast function. The purpose of this study was to test that C terminus of Hsc70-interacting protein (CHIP) has a specific role in suppressing the osteogenic activity of osteoblasts under inflammatory conditions. C2C12, MC3T3-E1 and HEK293T cell lines were cultured and cotransfected with related plasmids. After transfection, the cells were cultured further in the presence or absence of murine TNF-α and subjected to real time RT-PCR, Western blot, Ubiquitination assay, Co-immunoprecipitation, Luciferase reporter assay, Small interfering RNAs and Mineralization assay. The expression levels of TNF-α-induced CHIP and Osx were examined by RT-PCR and Western blot analysis. Co-immunoprecipitation and ubiquitination assays revealed ubiquitinated Osx, confirmed that CHIP indeed interacted with Osx and identified K55 and K386 residues as the ubiquitination sites in Osx, Luciferase reporter assay and Small interfering RNAs examined whether TNF-α target the bone morphogenetic protein signalling through CHIP. We established stable cell lines with the overexpression of HA-CHIP, Mineralization assay and CHIP siRNA demonstrated the important roles of CHIP on osteoblast function in conditions in which TNF-α is overexpressed. We found that the K55 and K386 residues are ubiquitination site(s) in Osx, and that TNF-α inhibits osteoblast differentiation by promoting Osx degradation through up-regulation of E3 ubiquitin ligase CHIP in osteoblast. Thus, CHIP targets Osx for ubiquitination and degradation in osteoblasts after chronic exposure to TNF-α, and inhibition of CHIP expression in osteoblasts may be a new mechanism to limit inflammation-mediated osteoporosis by promoting their differentiation into osteoblasts.

show abstract

Section: Discussionmentioning

confidence: 90%

Identification of C‐terminal Hsp70‐interacting protein as a mediator of tumour necrosis factor action in osteoblast differentiation by targeting osterix for degradation

Xie

2015

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…There is compelling evidence that PINK1 and Parkin can function in a common pathway because Parkin overexpression can rescue the mitochondrial dysfunction and flight muscle degeneration phenotypes of PINK1 null Drosophila (Clark et al 2006; Park et al 2006; Yang et al 2006) and because PINK1-mediated phosphorylation of Parkin at serine 65 activates Parkin in vitro and PINK1-phosphorylated ubiquitin chains function both as receptors for recruiting Parkin from the cytosol to the mitochondrial outer membrane and as enhancers of Parkin’s E3 ligase activity (Kondapalli et al 2012; Shiba-Fukushima et al 2012; Caulfield et al 2014; Kane et al 2014; Kazlauskaite et al 2014a; Kazlauskaite et al 2014b; Koyano et al 2014; Ordureau et al 2014; Sauve and Gehring 2014; Shiba-Fukushima et al 2014; Caulfield et al 2015; Fiesel et al 2015a; Kazlauskaite et al 2015; Okatsu et al 2015a; Okatsu et al 2015b; Ordureau et al 2015a; Ordureau et al 2015b; Wauer et al 2015a; Wauer et al 2015b; Zheng and Hunter 2015). Nevertheless, multiple groups have published data indicating that PINK1 and Parkin can also function independently and in other pathways.…”

Section: Alternative Functions and Potential Pathogenic Mechanismsmentioning

confidence: 99%

Parkin and PINK1 functions in oxidative stress and neurodegeneration

Barodia

Creed

Goldberg

2017

Brain Research Bulletin

128

View full text Add to dashboard Cite

Loss-of-function mutations in the genes encoding Parkin and PINK1 are causally linked to autosomal recessive Parkinson’s disease (PD). Parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial-targeted kinase, function together in a common pathway to remove dysfunctional mitochondria by autophagy. Presumably, deficiency for Parkin or PINK1 impairs mitochondrial autophagy and thereby increases oxidative stress due to the accumulation of dysfunctional mitochondria that release reactive oxygen species. Parkin and PINK1 likely have additional functions that may be relevant to the mechanisms by which mutations in these genes cause neurodegeneration, such as regulating inflammation, apoptosis, or dendritic morphogenesis. Here we briefly review what is known about functions of Parkin and PINK1 related to oxidative stress and neurodegeneration.

show abstract

“…Parkin activation requires phosphorylation of its ubiquitin-like domain by PINK1, which allows binding to PINK1-phosphorylated ubiquitin. It is believed that the role of phosphorylated ubiquitin is to interact with Parkin, thus releasing Parkin’s autoinhibitory domain [ 19 ] and exposing the ubiquitin ligase active site, allowing the enzyme to ubiquitinate multiple mitochondrial proteins [ 20 ]. In addition to phosphorylating free ubiquitin, PINK1 also phosphorylates poly-ubiquitin chains conjugated to mitochondrial proteins by Parkin.…”

Section: Regulation Of Mitophagy By Mitochondrial Protein Import Effimentioning

confidence: 99%

Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection

Pellegrino

Haynes

2015

BMC Biol

View full text Add to dashboard Cite

Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions. Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson’s disease, as well as bacterial infection. Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPRmt) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.

show abstract

Phosphorylated ubiquitin: a new shade of PINK1 in Parkin activation

Cited by 11 publications

References 12 publications

Identification of C‐terminal Hsp70‐interacting protein as a mediator of tumour necrosis factor action in osteoblast differentiation by targeting osterix for degradation

Identification of C‐terminal Hsp70‐interacting protein as a mediator of tumour necrosis factor action in osteoblast differentiation by targeting osterix for degradation

Parkin and PINK1 functions in oxidative stress and neurodegeneration

Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection

Contact Info

Product

Resources

About