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Tracing the evolution of novel features of human Toll-like receptor 4.

ABSTRACT: Toll-like receptor 4 (TLR4) is a critical innate immune protein that activates inflammation in response to extracellular cues. Much of the work to understand how the protein works in humans has been done using mouse models. Although human and mouse TLR4 have many shared features, they have also diverged significantly since their last common ancestor, acquiring 277 sequence differences. Functional differences include the extent of ligand-independent activation, whether lipid IVa acts as an antagonist or agonist, and the relative species cross-compatibility of their MD-2 cofactor. We set out to understand the evolutionary origins for these functional differences between human and mouse TLR4. Using a combination of phylogenetics, ancestral sequence reconstruction, and functional characterization, we found that evolutionary changes to the human TLR4, rather than changes to the mouse TLR4, were largely responsible for these functional changes. Human TLR4 repressed ancestral ligand-independent activity and gained antagonism to lipid IVa. Additionally, mutations to the human TLR4 cofactor MD-2 led to lineage-specific incompatibility between human and opossum TLR4 complex members. These results were surprising, as mouse TLR4 has acquired many more mutations than human TLR4 since their last common ancestor. Our work has polarized this set of transitions and sets up work to study the mechanistic underpinnings for the evolution of new functions in TLR4.

SUBMITTER: Anderson JA

PROVIDER: S-EPMC6566505 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Tracing the evolution of novel features of human Toll-like receptor 4.

Anderson Jeremy A JA Loes Andrea N AN Waddell Grace L GL Harms Michael J MJ

Protein science : a publication of the Protein Society 20190603 7

Toll-like receptor 4 (TLR4) is a critical innate immune protein that activates inflammation in response to extracellular cues. Much of the work to understand how the protein works in humans has been done using mouse models. Although human and mouse TLR4 have many shared features, they have also diverged significantly since their last common ancestor, acquiring 277 sequence differences. Functional differences include the extent of ligand-independent activation, whether lipid IVa acts as an antago ...[more]

PMID: 31075178

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Project description:The genome sequence of the purple sea urchin, Strongylocentrotus purpuratus, a large and long-lived invertebrate, provides a new perspective on animal immunity. Analysis of this genome uncovered a highly complex immune system in which the gene families that encode homologs of the pattern recognition receptors that form the core of vertebrate innate immunity are encoded in large multigene families. The sea urchin genome contains 253 Toll-like receptor (TLR) sequences, more than 200 Nod-like receptors and 1095 scavenger receptor cysteine-rich domains, a 10-fold expansion relative to vertebrates. Given their stereotypic protein structure and simple intron-exon architecture, the TLRs are the most tractable of these families for more detailed analysis. A role for these receptors in immune defense is suggested by their similarity to TLRs in other organisms, sequence diversity, and expression in immunologically active tissues, including phagocytes. The complexity of the sea urchin TLR multigene families is largely derived from expansions independent of those in vertebrates and protostomes, although a small family of TLRs with structure similar to that of Drosophila Toll can be traced to an ancient eumetazoan ancestor. Several other echinoderm sequences are now available, including Lytechinus variegatus, as well as partial sequences from two other sea urchin species. Here, we present an analysis of the invertebrate deuterostome TLRs with emphasis on the echinoderms. Representatives of most of the S. purpuratus TLR subfamilies and homologs of the mccTLR sequences are found in L. variegatus, although the L. variegatus TLR gene family is notably smaller (68 TLR sequences). The phylogeny of these genes within sea urchins highlights lineage-specific expansions at higher resolution than is evident at the phylum level. These analyses identify quickly evolving TLR subfamilies that are likely to have novel immune recognition functions and other, more stable, subfamilies that may function more similarly to those of vertebrates.

Dataset Information

Tracing the evolution of novel features of human Toll-like receptor 4.

Publications

Tracing the evolution of novel features of human Toll-like receptor 4.

Similar Datasets

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