Supplementary Figure 6: Proposed model for rLCx-mediated resolution of IMD pathway activation.
From: The regulatory isoform rPGRP-LC induces immune resolution via endosomal degradation of receptors
(a) During Gram-negative infection, TCT released from live bacteria efficiently activates the IMD pathway by engaging PGRP-LCx-LCa homodimers (as opposed to PGRP-LC-rLC heterodimers). Since ligand binding depends on the ectodomains alone, homodimers and heterodimers of activating and regulatory isoforms are equally likely to assemble. IMD recruitment requires dimerization of activating receptors, therefore neither rLC-rLC homodimers nor rLC-LC heterodimers can activate the pathway. In this sense, rLC acts similarly to PGRP-LF with regards to TCT: it can form ligand-bound dimers with LC but cannot signal 18. IMD pathway activation triggers transcriptional induction of antimicrobial peptide genes and the production of negative regulators of the pathway, such as rLC. (b) Once bacteria are killed, the balance of available ligands shifts from TCT monomers to PGN polymers, which can recruit both activating PGRP-LC and regulatory rPGRP-LC isoforms in one complex. rPGRP-LC promotes ESCRT-mediated clearance of signalling complexes. Components of the ESCRT machinery capture signalling receptors, trafficking them into multivesicular bodies, from where the cytosolic tails can no longer interact with signalling adaptors. Receptors are eventually degraded to resolve IMD pathway activation. Note that the intracellular negative regulator Pirk (not shown) contributes to regulation in both scenarios, regardless of the type of ligand.
