Abstract
Protein AMPylation by Fic domain-containing proteins (Fic proteins) is an ancient and conserved post-translational modification of mostly unexplored significance. Here we characterize the Caenorhabditis elegans Fic protein FIC-1 in vitro and in vivo. FIC-1 is an AMPylase that localizes to the nuclear surface and modifies core histones H2 and H3 as well as heat shock protein 70 family members and translation elongation factors. The three-dimensional structure of FIC-1 is similar to that of its human ortholog, HYPE, with 38% sequence identity. We identify a link between FIC-1-mediated AMPylation and susceptibility to the pathogen Pseudomonas aeruginosa, establishing a connection between AMPylation and innate immunity in C. elegans.
Highlights
How post-translational modifications regulate protein activity is a fundamental question in biology
Investigating the consequence of diminished (fic-1(n5823)) or increased (FIC-1[E274G](nIs733)) AMPylation levels in vivo, we find a link between AMPylation and the innate immune response to the bacterial pathogen P. aeruginosa, describing a novel in vivo phenotype associated with Fic protein mediated target AMPylation
We performed longevity assays to evaluate whether changes in FIC-1 activity might affect lifespan and observed no significant differences between fic-1(n5823) mutants, and FIC-1[E274G](nIs733) constitutively active animals or wild type controls at 20°C or 25°C (Fig 1A–1D, additional independent replicate shown in S8A–S8C Fig)
Summary
How post-translational modifications regulate protein activity is a fundamental question in biology. AMPylation, the covalent addition of AMP to a target protein, has recently been described as a new post-translational modification found in both prokaryotes and eukaryotes. While many bacterial species encode a number of different Fic proteins, most eukaryotes,— including Caenorhabditis elegans, Drosophila melanogaster, Mus musculus and Homo sapiens— carry only a single gene that specifies a Fic family member. Several pathogens evolved effector proteins equipped with Fic-domains that— upon translocation into the host cell—interfere with host cell signaling. They do so by covalently AMPylating and inactivating small GTPases of the Rho and Rab family [11, 12]
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