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Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule.

ABSTRACT: Programmed cell death 1 (PD-1) is an immune checkpoint molecule regulating T-cell function. Preventing PD-1 binding to its ligand PD-L1 has emerged as an important tool in immunotherapy. Here, we describe a unique human catalytic antibody light chain, H34, which mediates enzymatic degradation of human PD-1 peptides and recombinant human PD-1 protein and thus functions to prevent the binding of PD-1 with PD-L1. H34 degraded one half of the PD-1 molecules within about 6 h under the experimental conditions. Investigating the acquisition of the catalytic function by H34, which belongs to subgroup I and lacks a Pro⁹⁵ residue in CDR-3, revealed the importance of this sequence, as a Pro⁹⁵-reconstituted mutant (H34-Pro⁹⁵(+)) exhibited very little catalytic activity to cleave PD-1. Interestingly, EDTA inhibited the catalytic activity of H34, which could work as a metallo-protease. Zn²⁺ or Co²⁺ ions may work as a cofactor. It is meaningfull that H34 was obtained from the human antibody gene taken from a healthy volunteer, suggesting that we potentially have such unique molecules in our body.

SUBMITTER: Hifumi E

PROVIDER: S-EPMC8341958 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule.

Hifumi Emi E Taguchi Hiroaki H Nonaka Tamami T Harada Takunori T Uda Taizo T

RSC chemical biology 20201210 1

Programmed cell death 1 (PD-1) is an immune checkpoint molecule regulating T-cell function. Preventing PD-1 binding to its ligand PD-L1 has emerged as an important tool in immunotherapy. Here, we describe a unique human catalytic antibody light chain, H34, which mediates enzymatic degradation of human PD-1 peptides and recombinant human PD-1 protein and thus functions to prevent the binding of PD-1 with PD-L1. H34 degraded one half of the PD-1 molecules within about 6 h under the experimental co ...[more]

PMID: 34458785

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Project description:Excessive application of the herbicide chlorimuron-ethyl (CE) severely harms subsequent crops and poses severe risks to environmental health. Therefore, methods for efficiently decreasing and eliminating CE residues are urgently needed. Microbial consortia show potential for bioremediation due to their strong metabolic complementarity and synthesis. In this study, a microbial consortium entitled L1 was enriched from soil contaminated with CE by a "top-down" synthetic biology strategy. The consortium could degrade 98.04% of 100 mg L-1 CE within 6 days. We characterized it from the samples at four time points during the degradation process and a sample without degradation activity via metagenome and 16S rDNA sequencing. The results revealed 39 genera in consortium L1, among which Methyloversatilis (34.31%), Starkeya (28.60%), and Pseudoxanthomonas (7.01%) showed relatively high abundances. Temporal succession and the loss of degradability did not alter the diversity and community composition of L1 but changed the community structure. Taxon-functional contribution analysis predicted that glutathione transferase [EC 2.5.1.18], urease [EC 3.5.1.5], and allophanate hydrolase [EC 3.5.1.54] are relevant for the degradation of CE and that Methyloversatilis, Pseudoxanthomonas, Methylopila, Hyphomicrobium, Stenotrophomonas, and Sphingomonas were the main degrading genera. The degradation pathway of CE by L1 may involve cleavage of the CE carbamide bridge to produce 2-amino-4-chloro-6-methoxypyrimidine and ethyl o-sulfonamide benzoate. The results of network analysis indicated close interactions, cross-feeding, and co-metabolic relationships between strains in the consortium, and most of the above six degrading genera were keystone taxa in the network. Additionally, the degradation of CE by L1 required not only "functional bacteria" with degradation capacity but also "auxiliary bacteria" without degradation capacity but that indirectly facilitate/inhibit the degradation process; however, the abundance of "auxiliary bacteria" should be controlled in an appropriate range. These findings improve the understanding of the synergistic effects of degrading bacterial consortia, which will provide insight for isolating degrading bacterial resources and constructing artificial efficient bacterial consortia. Furthermore, our results provide a new route for pollution control and biodegradation of sulfonylurea herbicides.

Dataset Information

Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule.

Publications

Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule.

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