Lipin-2 degradation elicits a proinflammatory gene signature in macrophages

Biochem Biophys Res Commun. 2020 Apr 2;524(2):477-483. doi: 10.1016/j.bbrc.2020.01.119. Epub 2020 Jan 31.

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.

Keywords: IL-1β; Inflammation; Lipin-2; MLN4924; Ubiquitination; β-TRCP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Macrophages / metabolism*
  • Mice
  • Phosphatidate Phosphatase / genetics
  • Phosphatidate Phosphatase / metabolism*
  • Proteolysis*
  • RAW 264.7 Cells
  • Ubiquitination
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism

Substances

  • beta-Transducin Repeat-Containing Proteins
  • Phosphatidate Phosphatase
  • Lipin 2 protein, mouse