The LPS-responsive ADP-ribosylated proteome

Authors

• CM Daniels
• AG Nuccio
• A Nita-Lazar

Abstract

ADP-ribosylation is a protein post-translational modification (PTM) which has primarily been characterized as an important regulator of DNA damage repair and cell death. The importance of this PTM has been highlighted by clinical inhibition of poly(ADP-ribose) polymerases (PARPs) – the enzymes responsible for ADP-ribosylation – an approach which has proven effective in combating a growing number of cancers. These PARP inhibitors (PARPi) have also shown promise for the treatment of immune-related disorders such as rheumatoid arthritis, Crohn’s disease, and sepsis, though the mechanism of action is not well understood. Here we have shown that PARP inhibitors decrease the release of pro-inflammatory cytokines from LPS-stimulated macrophages, a finding which suggests that ADP-ribosylation is involved in the TLR4 response to LPS. In order to gain a mechanistic understanding of this regulation we have characterized the ADP-ribosylated proteome in human and mouse macrophages both before and during LPS-mediated activation. The resulting database of over 1000 ADP-ribosylation sites provides a first look at site-specific ADP-ribosylation in macrophages, and highlights the dynamic nature of this PTM during activation of the innate immune response. LPS-sensitive ADP-ribosylation of proteins known to regulate the MAP kinase cascade and NF¿B signaling has warranted careful, targeted follow-up by our group. We will discuss the details of these mechanistic studies, and their potential implications for the use of PARP inhibitors for the treatment of immune disorders. This research was supported by the Intramural Research Program of NIAID, NIH.

Scientific Focus Area: Immunology

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