Origin and Evolution of Two Independently Duplicated Genes Encoding UDP- Glucose: Glycoprotein Glucosyltransferases inCaenorhabditisand Vertebrates

Abstract

UDP-glucose: glycoprotein glucosyltransferase (UGGT) is a protein that operates as the gatekeeper for the endoplasmic reticulum (ER) quality control mechanism of glycoprotein folding. It is known that vertebrates and Caenorhabditis genomes harbor two uggt gene copies that exhibit differences in their properties.Bayesian phylogenetic inference based on 195 UGGT and UGGT-like protein sequences of an ample spectrum of eukaryotic species showed that uggt genes went through independent duplications in Caenorhabditis and vertebrates. In both lineages, the catalytic domain of the duplicated genes was subjected to a strong purifying selective pressure, while the recognition domain was subjected to episodic positive diversifying selection. Selective relaxation in the recognition domain was more pronounced in Caenorhabditis uggt-b than in vertebrates uggt-2. Structural bioinformatics analysis revealed that Caenorhabditis UGGT-b protein lacks essential sequences proposed to be involved in the recognition of unfolded proteins. When we assayed glucosyltrasferase activity of a chimeric protein composed by Caenorhabditis uggt-b recognition domain fused to S. pombe catalytic domain expressed in yeast, no activity was detected.The present results support the conservation of the UGGT activity in the catalytic domain and a putative divergent function of the recognition domain for the UGGT2 protein in vertebrates, which would have gone through a specialization process. In Caenorhabditis, uggt-b evolved under different constraints compared to uggt-a which, by means of a putative neofunctionalization process, resulted in a non-redundant paralog. The non-canonical function of uggt-b in the worm lineage highlights the need to take precautions before generalizing gene functions in model organisms. KEYWORDS

Selective involvement of UGGT variant: UGGT2 in protecting mouse embryonic fibroblasts from saturated lipid-induced ER stress

“…The Uggt gene is highly conserved across eukaryotes, but only in vertebrates and Caenorhabditis an independent gene duplication event occurred ( 11 , 12 ). In both cases, the duplicated genes retained the glucosyl transferase function of the C-terminal catalytic domain, while the N-terminal recognition domain was subjected to extensive alterations.…”

“…In Caenorhabditis , the current consensus suggests that the paralogous uggt genes have a divergent, nonredundant, ER stress-related function. Given the strong purifying selective pressure on the vertebrate Uggt gene, it has been proposed that Uggt2 also has to benefit the survival of the host organism ( 11 ). While UGGT1 preferentially recognizes and glucosylates misfolded proteins, our in vitro results demonstrate that UGGT2 recognizes and glucosylates sPA, a lipid.…”

“…While UGGT1 preferentially recognizes and glucosylates misfolded proteins, our in vitro results demonstrate that UGGT2 recognizes and glucosylates sPA, a lipid. Considering the reduced viability of UGGT2 KO MEFs under DTT-induced lipid bilayer stress, an increasingly similar picture in invertebrates compared to Caenorhabditis arises, suggesting a divergent, nonredundant, ER stress-related function of the vertebrate UGGT paralogues ( 11 ).…”

“…The importance of UGGT1 in PQC and its role in mitigating ER stress is widely accepted. The biological function of UGGT1’s paralogue, UDP-glucose:glycoprotein glucosyltransferase 2 (UGGT2), remains less well defined ( 11 , 12 ), even though it has been recently proposed to play an important role in the maturation of some lysosomal proteins ( 13 ). A variety of clinical studies have reported changes in UGGT2 expression, such as elevated UGGT2 levels in the prefrontal cortex of schizophrenia patients ( 14 , 15 ).…”

Three rare dioecious Caenorhabditis nematode species (C. Tribulationis, C. Yunquensis, and C. Zanzibari) do not live in the same habitats

“…The nematode genus Caenorhabditis is tiny (~1 mm) and plays a role in understanding basic concepts of biological issues concerning evolution, for example, genomic and proteomic comparison (Crombie et al, 2019;Stevens et al, 2019;Caro et al, 2022), genome (Adams et al, 2023), sexual dimorphism (Le et al, 2017), and diversity, for example, adaptation (Caraballo et al, 2020;Caraballo et al, 2021).…”