Abstract
LAPTM5 (lysosomal-associated protein transmembrane 5) is a protein that is preferentially expressed in immune cells, and it interacts with the Nedd4 family of ubiquitin ligases. Recent studies in T and B cells identified LAPTM5 as a negative regulator of T and B cell receptor levels at the plasma membrane. Here we investigated the function of LAPTM5 in macrophages. We demonstrate that expression of LAPTM5 is required for the secretion of proinflammatory cytokines in response to Toll-like receptor ligands. We also show that RAW264.7 cells knocked down for LAPTM5 or macrophages from LAPTM5(-/-) mice exhibit reduced activation of NF-κB and MAPK signaling pathways mediated by the TNF receptor, as well as multiple pattern recognition receptors in various cellular compartments. TNF stimulation of LAPTM5-deficient macrophages leads to reduced ubiquitination of RIP1 (receptor-interacting protein 1), suggesting a role for LAPTM5 at the receptor-proximate level. Interestingly, we find that macrophages from LAPTM5(-/-) mice display up-regulated levels of A20, a ubiquitin-editing enzyme responsible for deubiquitination of RIP1 and subsequent termination of NF-κB activation. Our studies thus indicate that, in contrast to its negative role in T and B cell activation, LAPTM5 acts as a positive modulator of inflammatory signaling pathways and hence cytokine secretion in macrophages. They also highlight a role for the endosomal/lysosomal system in regulating signaling via cytokine and pattern recognition receptors.
Highlights
The late endosomal/lysosomal transmembrane protein LAPTM5 is expressed in hematopoietic cells
We show that RAW264.7 cells knocked down for LAPTM5 or macrophages from LAPTM5؊/؊ mice exhibit reduced activation of nuclear factor-B (NF-B) and MAPK signaling pathways mediated by the TNF receptor, as well as multiple pattern recognition receptors in various cellular compartments
We demonstrate that LAPTM5 is a positive regulator of NF-B and MAPK signaling that allows efficient proinflammatory cytokine production in response to several inducers of macrophage activation
Summary
The late endosomal/lysosomal transmembrane protein LAPTM5 is expressed in hematopoietic cells. We show that RAW264.7 cells knocked down for LAPTM5 or macrophages from LAPTM5؊/؊ mice exhibit reduced activation of NF-B and MAPK signaling pathways mediated by the TNF receptor, as well as multiple pattern recognition receptors in various cellular compartments. Our studies indicate that, in contrast to its negative role in T and B cell activation, LAPTM5 acts as a positive modulator of inflammatory signaling pathways and cytokine secretion in macrophages. They highlight a role for the endosomal/lysosomal system in regulating signaling via cytokine and pattern recognition receptors
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