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Meschede, Jens; Sadic, Maria; Furthmann, Nikolas; Miedema, Tim; Sehr, Dominik A.; Müller-Rischart, A. Kathrin; Bader, Verian; Berlemann, Lena A.; Pilsl, Anna; Schlierf, Anita; Barkovits, Katalin; Kachholz, Barbara; Rittinger, Katrin; Ikeda, Fumiyo; Marcus, Katrin; Schaefer, Liliana; Tatzelt, Jörg and Winklhofer, Konstanze F. (2020): The parkin-coregulated gene product PACRG promotes TNF signaling by stabilizing LUBAC. In: Science Signaling, Vol. 13, No. 617, eaav1256

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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 kappa B (NF-kappa B) activation in response to TNF. TNF-induced nuclear translocation of the NF-kappa B subunit p65 and NF-kappa B-dependent transcription were decreased in PACRG-deficient cells. Defective canonical NF-kappa B 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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