Functional conservation of an ancestral Pellino protein in helminth species

Abstract

The immune system of H. sapiens has innate signaling pathways that arose in ancestral species. This is exemplified by the discovery of the Toll-like receptor (TLR) pathway using free-living model organisms such as Drosophila melanogaster. The TLR pathway is ubiquitous and controls sensitivity to pathogen-associated molecular patterns (PAMPs) in eukaryotes. There is, however, a marked absence of this pathway from the plathyhelminthes, with the exception of the Pellino protein family, which is present in a number of species from this phylum. Helminth Pellino proteins are conserved having high similarity, both at the sequence and predicted structural protein level, with that of human Pellino proteins. Pellino from a model helminth, Schistosoma mansoni Pellino (SmPellino), was shown to bind and poly-ubiquitinate human IRAK-1, displaying E3 ligase activity consistent with its human counterparts. When transfected into human cells SmPellino is functional, interacting with signaling proteins and modulating mammalian signaling pathways. Strict conservation of a protein family in species lacking its niche signalling pathway is rare and provides a platform to examine the ancestral functions of Pellino proteins that may translate into novel mechanisms of immune regulation in humans.

The Emerging Roles of Pellino Family in Pattern Recognition Receptor Signaling

“…In the Drosophila genome, Pellino interacts with and regulates plasma membrane MyD88-K48-Ub turnover to balance Toll-mediated immune signaling positively or negatively (52,53). An ancestral Pellino protein from helminth species binding and poly-ubiquitinating human IRAK1 displays its E3 ligase activity and conservative function (54). In mammals, the production of proinflammatory interleukin-1 b (IL-1b), IL-6, C-X-C motif chemokine ligand 8 (CXCL8), and IFNs regulated by Pellino1, Pellino2, and Pellino3 demonstrate the key roles of the Pellino family in TLR/IL-1R signaling (25,(55)(56)(57).…”

Bioactive Excreted/Secreted Products of Entomopathogenic Nematode Heterorhabditis bacteriophora Inhibit the Phenoloxidase Activity during the Infection

“…By this mechanism, Pellino participates in a negative feedback loop that regulates the activity of the Toll pathway. Moreover, Pellino is a highly conserved protein and has been found in several species, including helminths, insects and humans [ 82 , 83 , 86 ]. The Pellino protein from the human parasite Schistosoma mansoni was shown to bind and poly-ubiquitinate human IRAK-1, a serine/threonine kinase associated with the interleukin-1 receptor in a Toll-like pathway.…”

Pellino Proteins in Viral Immunity and Pathogenesis

“…The individual signaling cascades and the involvement of specific Pellino proteins are more comprehensively reviewed elsewhere [3,4]. In addition to Drosophila, Pellino has also been identified in nematodes, including Caenorhabditis elegans and Schistosoma mansoni [8,9], as well as in several crustacean species [10][11][12][13]. In mammals, the three PELI genes encode the proteins Pellino1, Pellino2, and Pel-lino3 (Figure 2) [13].…”

“…In addition to Drosophila, Pellino has also been identified in nematodes, including Caenorhabditis elegans and Schistosoma mansoni [ 8 , 9 ], as well as in several crustacean species [ 10 , 11 , 12 , 13 ]. In mammals, the three PELI genes encode the proteins Pellino1, Pellino2, and Pellino3 ( Figure 2 ) [ 13 ].…”