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LAPTM5 protein is a positive regulator of proinflammatory signaling pathways in macrophages

Wioletta K Glowacka1, Philipp Alberts, Rika Ouchida

  • 1Program in Cell Biology, the Hospital for Sick Children, and Biochemistry Department, University of Toronto, Toronto, Ontario M5G 1L7, Canada.

The Journal of Biological Chemistry
|June 27, 2012
PubMed

Insights

Lysosomal-associated protein transmembrane 5 (LAPTM5) positively regulates inflammatory signaling in macrophages, promoting cytokine secretion. This contrasts with its inhibitory role in T and B cells, highlighting LAPTM5

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Lysosomal-associated protein transmembrane 5 (LAPTM5) is expressed in immune cells and interacts with Nedd4 ubiquitin ligases.
  • Previous studies identified LAPTM5 as a negative regulator of T and B cell receptor levels.
  • The function of LAPTM5 in macrophages remained largely unexplored.

Purpose of the Study:

  • To investigate the role of LAPTM5 in macrophage inflammatory responses.
  • To elucidate the molecular mechanisms underlying LAPTM5-mediated regulation of signaling pathways in macrophages.

Main Methods:

  • Investigated LAPTM5 function in RAW264.7 cells with knockdown and in LAPTM5-deficient (LAPTM5(-/-)) mouse macrophages.
  • Analyzed cytokine secretion, NF-κB and MAPK pathway activation, and RIP1 ubiquitination.
  • Assessed the expression of A20, a key regulator of NF-κB signaling.

Main Results:

  • LAPTM5 expression is required for proinflammatory cytokine secretion in response to Toll-like receptor ligands.
  • LAPTM5 deficiency reduced NF-κB and MAPK pathway activation mediated by TNF receptor and pattern recognition receptors.
  • LAPTM5-deficient macrophages showed reduced RIP1 ubiquitination and increased A20 levels, suggesting LAPTM5 acts at the receptor-proximate level.
  • LAPTM5 functions as a positive modulator of inflammatory signaling in macrophages.

Conclusions:

  • LAPTM5 is a positive regulator of inflammatory signaling and cytokine secretion in macrophages, contrasting its role in T and B cells.
  • LAPTM5 influences inflammatory signaling by affecting RIP1 ubiquitination and A20 levels.
  • The endosomal/lysosomal system, through LAPTM5, plays a crucial role in regulating signaling pathways activated by cytokine and pattern recognition receptors.

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