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Cited by 2Wnt/β-catenin signaling in development and cancerBacterial Genetics and BiotechnologyLipid metabolism and biosynthesis

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The lipocone superfamily, a unifying theme in metabolism of lipids, peptidoglycan and exopolysaccharides, inter-organismal conflicts and immunity

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Burroughs, A Maxwell, Nicastro, Gianlucca G, Aravind, L·2025·eLife
DOI 10.7554/elife.108061PMC PMC12419801

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Abstract

Wnt proteins are critical signaling molecules in developmental processes across animals. Despite intense study, their evolutionary roots have remained enigmatic. Using sensitive sequence analysis and structure modeling, we establish that the Wnts are part of a vast assemblage of domains, the Lipocone superfamily, defined here for the first time. It includes previously studied enzymatic domains like the phosphatidylserine synthases (PTDSS1/2) and the TelC toxin domain from Streptococcus intermedius , the enigmatic VanZ proteins, the animal Serum Amyloid A (SAA), and a further host of uncharacterized proteins in a total of 30 families. Although the metazoan Wnts are catalytically inactive, we present evidence for a conserved active site across this superfamily, versions of which are consistently predicted to operate on head groups of either phospholipids or polyisoprenoid lipids, catalyzing transesterification and phosphate-containing head group cleavage reactions. We argue that this superfamily originated as membrane proteins, with one branch (including Wnt and SAA) evolving into diffusible versions. By comprehensively analyzing contextual information networks derived from comparative genomics, we establish that they act in varied functional contexts, including regulation of membrane lipid composition, extracellular polysaccharide biosynthesis, and biogenesis of bacterial outer-membrane components, like lipopolysaccharides. On multiple occasions, members of this superfamily, including the bacterial progenitors of Wnt and SAA, have been recruited as effectors in biological conflicts spanning inter-organismal interactions and anti-viral immunity in both prokaryotes and eukaryotes. These findings establish a unifying theme in lipid biochemistry, explain the origins of Wnt signaling, and provide new leads regarding immunity across the tree of life.

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Metadata

Authors
Burroughs, A. M., Nicastro, G. G., & Aravind, L.
Affiliations
National Institutes of Health (US)
Corresponding author
Aravind, L
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2025-09-09
Volume
14
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.108061
PMC
PMC12419801
OpenAlex
W4412554133
Cited by
2
References
7
Citations by year
2026: 1 · 2025: 1
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, public-domain)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Division of Intramural Research at the National Library of Medicine
  • National Institutes of Health
  • Oak Ridge Institute for Science and Education
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
Wnt proteins, phosphatidylserine synthase, serum amyloid A, transesterification, membrane lipid composition, exopolysaccharide biosynthesis, antiviral immunity, protein domain evolution, active site conservation
MeSH terms
Animals, Humans, Peptidoglycan, Lipid Metabolism

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