Evidence of an Antimicrobial Peptide Signature Encrypted in HECT E3 Ubiquitin Ligases

Abstract

The ubiquitin-proteasome pathway (UPP) is a hallmark of the eukaryotic cell. In jawed vertebrates, it has been co-opted by the adaptive immune system, where proteasomal degradation produces endogenous peptides for major histocompatibility complex class I antigen presentation. However, proteolytic products are also necessary for the phylogenetically widespread innate immune system, as they often play a role as host defense peptides (HDPs), pivotal effectors against pathogens. Here, we report the identification of the arachnid HDP oligoventin, which shares homology to a core member of the UPP, E3 ubiquitin ligases. Oligoventin has broad antimicrobial activity and shows strong synergy with lysozymes. Using computational and phylogenetic approaches, we show high conservation of the oligoventin signature in HECT E3s. In silico simulation of HECT E3s self-proteolysis provides evidence that HDPs can be generated by fine-tuned 26S proteasomal degradation, and therefore are consistent with the hypothesis that oligoventin is a cryptic peptide released by the proteolytic processing of an Nedd4 E3 precursor protein. Finally, we compare the production of HDPs and endogenous antigens from orthologous HECT E3s by proteasomal degradation as a means of analyzing the UPP coupling to metazoan immunity. Our results highlight the functional plasticity of the UPP in innate and adaptive immune systems as a possibly recurrent mechanism to generate functionally diverse peptides.

Effects of the Natural Peptide Crotamine from a South American Rattlesnake on Candida auris, an Emergent Multidrug Antifungal Resistant Human Pathogen

“…20100104268), essentially as previously described [9]. The other natural peptides evaluated here were isolated and characterized (sequence determination) essentially as previously described [25], and they were all produced by custom chemical synthesis (China Peptides Co., Shanghai, China). Peptide 1 (WRNWE-NH 2 , MW 788.35 Da) and peptide 2 (WRNWE, MW 789.35 Da) were initially identified in the hemolymph of centipedes, Scolopendra subspinipes (centipede/Chilopoda), while cheliferin (GAVLDIR, MW 742.4 Da) was from the pseudoscorpion Chelifer cancroides .…”

Biological consequences of structural and functional proteasome diversity

“…The peptide was shown to stimulate proteasome activity in cellular lysates and potentiate β5i subunit expression in conditions of IFN-γ stimulation ( Monte et al., 2017 ). Interestingly, several other UPS proteins were proposed as sources of bioactive peptides, for instance HECT E3 ubiquitin ligases ( Candido-Ferreira et al., 2016 ) and ubiquitin, fragments of latter possessing antimicrobial activity, were found in amniotic fluid of pregnant women (J. Y. Kim et al., 2007 ).…”

Two Tachykinin-Related Peptides with Antimicrobial Activity Isolated from Triatoma infestans Hemolymph

“…Antimicrobial peptides and proteins show a wide distribution and have been isolated from nearly all living organisms. [8][9][10][11][12][13][14][15][16][17][18][19][20][21] Beyond their antimicrobial effects, several AMPs have been shown to have other biological activities. 11,[22][23][24][25] One such protein group that represents the duplicity of activities for the same molecules is the tachykinin family.…”

“…[8][9][10][11][12][13][14][15][16][17][18][19][20][21] Beyond their antimicrobial effects, several AMPs have been shown to have other biological activities. 11,[22][23][24][25] One such protein group that represents the duplicity of activities for the same molecules is the tachykinin family. Tachykinins (TKs) form a family of neuropeptides in vertebrates, represented by compounds such as Neurokinin A, 26 Neurokinin B, 27 hemokinin/endokinin K, 28,29 and substance P (SP), which was the first TK discovered in alcoholic extracts of equine brain 30 and then isolated from the bovine hypothalamus.…”

“…Antimicrobial peptides and proteins show a wide distribution and have been isolated from nearly all living organisms. 8 - 21 …”