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TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy

ABSTRACT: Elevated or chronic innate immune activation plays a role in the progression of metabolic diseases such as diabetes, yet the influence of innate immune signaling on pancreatic β-cells is not well characterized. Here we report that TRAF6, an E3 ubiquitin ligase downstream of TLR signaling, maintains β-cell function during diet-induced obesity. Deletion or inhibition of TRAF6 impairs glucose homeostasis, mitochondrial function, and mitophagy during metabolic stress in both mouse and human islets. The combination of TRAF6 deficiency and palmitate exposure reduces localization of mitophagy machinery, such as BNIP3, to the mitochondria. Interestingly, co-deletion of Parkin restores glucose-stimulated insulin section, mitochondrial bioenergetics, and mitophagy. These findings suggest that Parkin-independent mitophagy mechanisms may be important for maintenance of β-cell function during metabolic stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE295268 | GEO | 2025/05/15

REPOSITORIES: GEO

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Project description:Purpose: The E3 ubiquitin ligase Parkin is a well-characterized regulator of mitochondrial autophagy (mitophagy); however, it is becoming increasingly appreciated to perform additional roles in various compartments of the cell. Our laboratory confirmed the presence of Parkin in the nucleus of various tissues (biochemical fractionations) and cell types (immunofluorescent imaging). Hypoxia-induced nuclear translocation of Parkin occured independent of the mitophagy regulator PINK1, and Parkinson's disease-associated mutants were restricted from the nuclueus. Accordingly, we inserted a nuclear localization sequence (NLS) at the n-terminus of Parkin and overexpressed both NLS Parkin and the wild-type protein in HeLa cells cultured at normoxia and hypoxia. Next-generation RNA-sequencing (RNA-seq) was used to determine the effect of nuclear Parkin on cellular transcription. Methods: mCherry-tagged NLS and wild-type Parkin were overexpressed in HeLa cells. Differential expression analyses were performed on Parkin vs. mCherry control cells and NLS Parkin vs. mCherry control cells at normoxia and following 12hr of hypoxia (n=3/group/condition). Paired-end sequencing was performed using the HiSeq4000. FastQC v0.11.3 was used for quality control, Trimmomatic v0.36 was used to trim reads which were aligned to the human genome (GRCh37.p13) using the STAR aligner v2.5.3a. Read quantification was performed with RSEM v 1.3.0 and the Gencode release 19. The R BioConductor packages edgeR and limma were used to implement the limma-voom method for differential expression analysis. Results: During normoxia, Parkin had no effect on basal transcription; however, overexpression of NLS Parkin was associated with 168 differentially expressed genes (DEGs: fold-change </= 1.5, FDR < 0.05) relative to mCherry control cells. Following hypoxia, the transcriptome associated with the overexpression of wild-type Parkin more closely resembled that of NLS Parkin. Along these lines, Parkin overexpression during hypoxia coincided with a total of 158 DEGs, 37% of which were shared with NLS Parkin. Overlapping and shared DEGs among Parkin and NLS Parkin were implicated in cellular metabolism, HIF1 signaling and survival. Our follow up co-immunoprecipitation and real-time quantitative PCR studies demonstrated that Parkin interacts with the Estrogen Related Receptor Alpha (ERRa) to promote the induction of its downstream target genes. Conclusions: Nuclear translocation of Parkin is a novel means by which this cytoprotective protein contributes to cellular homeostasis and especially critical during hypoxia.

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TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy

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