Adaptive evolution in two large families of ubiquitin-ligase adapters in nematodes and plants

Abstract

Host–pathogen arms races can result in adaptive evolution (positive selection) of host genes that mediate pathogen recognition and defense. To identify such genes in nematodes, I used maximum-likelihood analysis of codon evolution to survey all paralogous gene groups in Caenorhabditis elegans. This survey found robust evidence of positive selection in two classes of genes not previously implicated in pathogen defense. Both classes of genes encode ubiquitin-dependent proteasome adapters, which recruit diverse substrate proteins for poly-ubiquitination and proteolysis by Cullin-E3 ubiquitin-ligase complexes. The adapter proteins are members of the F-box superfamily and the MATH-BTB family, which consist of a conserved Cullin-binding domain and a variable substrate-binding domain. Further analysis showed that most of the ∼520 members of the F-box superfamily and ∼50 members of the MATH-BTB family in C. elegans are under strong positive selection at sites in their substrate-binding domains but not in their Cullin-binding domains. Structural modeling of positively selected sites in MATH-BTB proteins suggests that they are concentrated in the MATH peptide-binding cleft. Comparisons among three Caenorhabditis species also indicate an extremely high rate of gene duplication and deletion (birth–death evolution) in F-box and MATH-BTB families. Finally, I found strikingly similar patterns of positive selection and birth–death evolution in the large F-box superfamily in plants. Based on these patterns of molecular evolution, I propose that most members of the MATH-BTB family and the F-box superfamily are adapters that target foreign proteins for proteolysis. I speculate that this system functions to combat viral pathogens or bacterial protein toxins.

Evolution of F-box genes in plants: Different modes of sequence divergence and their relationships with functional diversification

“…If so, then we would expect that some F-box proteins have evolved under positive selection. Indeed, in nematodes and plants, it has been suggested that some F-box proteins evolved under positive selection at sites in substratebinding domains (33). However, we showed here that, because of the frequent frame-shift mutations caused by (pseudo)exonization and/or insertions/deletions, the C-terminal sequences may no longer be homologous even between closely related duplicate genes.…”

The SCFFSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans

“…[28][29][30] Inhibiting skr-1 or skr-7 by RNAi caused a significant increase in ENU-induced germ cell apoptosis similar to inactivating cul-1 or ned-8 ( Figure 2c and Supplementary Table 1). The increased apoptosis caused by inhibiting cul-1 or skr-1 was abolished in cep-1(gk138) mutants (Figure 2d), suggesting that these genes also act fsn-1 regulates cep-1-dependent signaling in response to DNA damage.…”

“…The specificity of SCF ligases is controlled by F-box proteins, which bind to distinct substrate proteins that are targeted for ubiquitin-mediated proteolysis. 26 We systematically inhibited 328 of the 520 predicted F-box genes 28 by RNAi and identified FSN-1, an F-box protein conserved from worm to human that physically associates with RPM-1, SKR-1, and CUL-1 to regulate neuromuscular synapse formation. 31 Using two different null alleles, fsn-1(hp1) and fsn-1(gk429), we confirmed that FSN-1 is a potent negative regulator of ENU-induced germ cell apoptosis ( Figure 3a).…”

Large-Scale, Lineage-Specific Expansion of a Bric-a-Brac/Tramtrack/Broad Complex Ubiquitin-Ligase Gene Family in Rice

“…Conversely, both rice and Arabidopsis lack the BTB-zinc finger and BTB-BACK-kelch combinations that comprise a substantial percentage of the vertebrate BTB collections (Aravind and Koonin, 1999;Prag and Adams, 2003;Stogios et al, 2005). Rice appears more like C. elegans with respect to the MATH-BTB family Stogios et al, 2005;Thomas, 2006), which is substantially larger relative to Arabidopsis, yeast, and vertebrates (Figure 1).…”

“…There is also evidence for large-scale expansions within specific BTB protein subtypes. C. elegans, for instance, has a much larger MATH-BTB family than is present in either insects or vertebrates (Stogios et al, 2005), and there have even been independent expansions of different subsets of the MATH-BTB protein family within individual Caenorhabditis species (Thomas, 2006). One hypothesis to explain this diversity is that each lineage mixed and matched various substrate binding domains with different E3 complex-interacting motifs (e.g., F-box and BTB domains) and then expanded and diversified specific subgroups to handle their own particular sets of Ub targets as each species evolved.…”