Lipin-2 degradation elicits a proinflammatory gene signature in macrophages

Asami Watahiki, Kouhei Shimizu, Seira Hoshikawa, Mitsuki Chiba, Hiroshi Kitamura, Hiroshi Egusa, Satoshi Fukumoto, Hiroyuki Inuzuka

Research output: Contribution to journalArticle

Abstract

Lipin-2 is a phosphatidate phosphatase with key roles in regulating lipid storage and energy homeostasis. LPIN2-genetic deficiency is associated with an autoinflammatory disorder, underscoring its critical role in innate immune signaling; however, the regulatory mechanisms underlying protein stability remain unknown. Here, we demonstrate that Lipin-2 interacts with β-TRCP, a substrate receptor subunit of the SCFβ - TRCP E3 ligase, and undergoes ubiquitination and proteasomal degradation. β-TRCP-knockout in RAW264.7 macrophages resulted in Lipin-2 accumulation, leading to the suppression of LPS-induced MAPK activation and subsequent proinflammatory gene expression. Consistent with this, treatment with MLN4924, a Cullin-neddylation inhibitor that suppresses SCF E3 activity, increased Lipin-2 protein and concomitantly decreased Il1b expression. These findings suggested that β-TRCP-mediated Lipin-2 degradation affects macrophage-elicited proinflammatory responses and could lead to new therapeutic approaches to treat inflammatory diseases.

Original languageEnglish
Pages (from-to)477-483
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume524
Issue number2
DOIs
Publication statusPublished - Apr 2 2020
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Watahiki, A., Shimizu, K., Hoshikawa, S., Chiba, M., Kitamura, H., Egusa, H., ... Inuzuka, H. (2020). Lipin-2 degradation elicits a proinflammatory gene signature in macrophages. Biochemical and Biophysical Research Communications, 524(2), 477-483. https://doi.org/10.1016/j.bbrc.2020.01.119