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

Jens Meschede, Maria Šadić, Nikolas Furthmann, Tim Miedema, Dominik A. Sehr, A. Kathrin Müller-Rischart, Verian Bader, Lena A. Berlemann, Anna Pilsl, Anita Schlierf, Katalin Barkovits, Barbara Kachholz, Katrin Rittinger, Fumiyo Ikeda, Katrin Marcus, Liliana Schaefer, Jörg Tatzelt, Konstanze F. Winklhofer

研究成果: Contribution to journalArticle査読

2 被引用数 (Scopus)

抄録

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.

本文言語英語
論文番号eaav1256
ジャーナルScience Signaling
13
617
DOI
出版ステータス出版済み - 2 4 2020
外部発表はい

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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