Cytokine receptors, such as tumor necrosis factor receptor I (TNFRI) and lymphotoxin β receptor (LTβR), activate inflammatory NF-κB signaling upon stimulation. We previously demonstrated that depletion of ESCRT components leads to endosomal accumulation of TNFRI and LTβR, and their ligand-independent signaling to NF-κB. Here, we studied if other perturbations of the endolysosomal system could trigger intracellular accumulation and signaling of ligand-free LTβR. While depletion of CORVET had no effect, knockdown of HOPS or Rab7, or pharmacological inhibition of lysosomal degradation, caused endosomal accumulation of LTβR and its increased interactions with TRAF2/TRAF3 signaling adaptors. However, the NF-κB pathway was not activated under these conditions. We found that knockdown of HOPS or Rab7 led to LTβR sequestration in intraluminal vesicles of endosomes, thus precluding NF-κB signaling. This was in contrast to LTβR localization on the outer endosomal membrane after ESCRT depletion that was permissive for signaling. We propose that the inflammatory response induced by intracellular accumulation of endocytosed cytokine receptors critically depends on the precise receptor topology within endosomal compartments.
The topology of lymphotoxin β receptor accumulated upon endolysosomal dysfunction dictates the NF-κB signaling outcome
These authors contributed equally to this work
Currently Viewing Accepted Manuscript - Newer Version Available
Magdalena Banach-Orłowska, Kamil Jastrzębski, Jarosław Cendrowski, Małgorzata Maksymowicz, Karolina Wojciechowska, Michał Korostyński, Dimitri Moreau, Jean Gruenberg, Marta Miaczynska; The topology of lymphotoxin β receptor accumulated upon endolysosomal dysfunction dictates the NF-κB signaling outcome. J Cell Sci 2018; jcs.218883. doi: https://doi.org/10.1242/jcs.218883
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