Research ArticleCell Biology

The parkin-coregulated gene product PACRG promotes TNF signaling by stabilizing LUBAC

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Science Signaling  04 Feb 2020:
Vol. 13, Issue 617, eaav1256
DOI: 10.1126/scisignal.aav1256

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Stabilizing LUBAC

The parkin-coregulated gene (PACRG) encodes a protein of unknown function and shares a promoter with parkin, which encodes an E3 ubiquitin ligase that induces the degradation of damaged mitochondria and promotes nuclear factor κB (NF-κB) signaling. Meschede et al. found that PACRG played no role in mitophagy in cultured human cells but did promote NF-κB signaling downstream of the tumor necrosis factor (TNF) receptor TNFR1. PACRG was recruited to the TNFR1 signaling complex and protected cells from TNF-induced apoptosis by interacting with and stabilizing the linear ubiquitin chain assembly complex (LUBAC). PACRG functionally substituted for the LUBAC component and adaptor protein SHARPIN. That Parkin and PACRG both promote NF-κB signaling is consistent with previous reports linking polymorphisms in the regulatory regions of both genes with increased susceptibility to infections with intracellular bacterial pathogens.

Abstract

The Parkin-coregulated gene (PACRG), which encodes a protein of unknown function, shares a bidirectional promoter with Parkin (PRKN), which encodes an E3 ubiquitin ligase. Because PRKN is important in mitochondrial quality control and protection against stress, we tested whether PACRG also affected these pathways in various cultured human cell lines and in mouse embryonic fibroblasts. PACRG did not play a role in mitophagy but did play a role in tumor necrosis factor (TNF) signaling. Similarly to Parkin, PACRG promoted nuclear factor κB (NF-κB) activation in response to TNF. TNF-induced nuclear translocation of the NF-κB subunit p65 and NF-κB–dependent transcription were decreased in PACRG-deficient cells. Defective canonical NF-κB activation in the absence of PACRG was accompanied by a decrease in linear ubiquitylation mediated by the linear ubiquitin chain assembly complex (LUBAC), which is composed of the two E3 ubiquitin ligases HOIP and HOIL-1L and the adaptor protein SHARPIN. Upon TNF stimulation, PACRG was recruited to the activated TNF receptor complex and interacted with LUBAC components. PACRG functionally replaced SHARPIN in this context. In SHARPIN-deficient cells, PACRG prevented LUBAC destabilization, restored HOIP-dependent linear ubiquitylation, and protected cells from TNF-induced apoptosis. This function of PACRG in positively regulating TNF signaling may help to explain the association of PACRG and PRKN polymorphisms with an increased susceptibility to intracellular pathogens.

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