Compositions and methods comprising histidyl-tRNA synthetase splice variants having non-canonical biological activities
Isolated histidyl-tRNA synthetase splice variant polynucleotides and polypeptides having non-canonical biological activities are provided, as well as compositions and methods related thereto.
1. An isolated histidyl-tRNA synthetase (HRS) splice variant polypeptide, for use in a method of reducing inflammatory activity wherein the HRS polypeptide is 50-175 amino acids in length and comprises at least 50 contiguous amino acids of SEQ ID NO: 6, or a variant thereof having at least 95% sequence identity to SEQ ID NO: 6, where the HRS polypeptide comprises a WHEP domain and lacks a functional aminoacylation domain.
2. The isolated HRS polypeptide of claim 1 , where the HRS polypeptide is up to about 70 amino acids in length.
3. The isolated HRS polypeptide of claim 2 , where the HRS polypeptide comprises the amino acid sequence of SEQ ID NO:6.
4. The isolated HRS polypeptide of claim 1 , where the HRS polypeptide is up to about 175 amino acids in length and comprises at least 120 contiguous amino acids of SEQ ID NO:9.
5. The isolated HRS polypeptide of claim 4 , where the HRS polypeptide comprises the amino acid sequence of SEQ ID NO:9.
6. The isolated HRS polypeptide of claim 1 , where the HRS polypeptide is about 60 amino acids in length and has at least 95% sequence identity to SEQ ID NO:6.
7. The isolated HRS polypeptide of claim 1 , where the HRS polypeptide is about 171 amino acids in length and has at least 95% sequence identity to SEQ ID NO:9.
8. The isolated HRS polypeptide of claim 1 , where the HRS polypeptide is about 60 amino acids in length and comprises the amino acid sequence of SEQ ID NO:6.
9. The isolated HRS polypeptide of claim 1 , where the HRS polypeptide is about 171 amino acids in length and comprises the amino acid sequence of SEQ ID NO:9.
10. An isolated histidyl-tRNA synthetase (HRS) splice variant polypeptide, for use in a method of reducing inflammatory activity wherein the HRS polypeptide comprises the amino acid sequence of SEQ ID NO: 11, or a variant thereof having at least 95% sequence identity to SEQ ID NO: 11, where the HRS polypeptide comprises a WHEP domain and lacks a functional aminoacylation domain.
11. The isolated HRS polypeptide of claim 10 , where the HRS polypeptide comprises the amino acid sequence of SEQ ID NO:11.
12. The isolated HRS polypeptide of claim 10 , where the HRS polypeptide is about 211 amino acids in length.
13. The isolated HRS polypeptide of claim 12 , where the HRS polypeptide has at least 95% sequence identity to SEQ ID NO:11.
14. The isolated HRS polypeptide of claim 12 , where the HRS polypeptide comprises the amino acid sequence of SEQ ID NO:11.
15. An isolated recombinant histidyl-tRNA synthetase (HRS) for use in a method of reducing inflammatory activity wherein the HRS polypeptide consists essentially of the amino acid sequence of SEQ ID NO: 6, 9 or 11.
16. The isolated HRS polypeptide of claim 1 , further comprising a heterologous fusion partner.
17. The isolated HRS polypeptide of claim 10 , further comprising a heterologous fusion partner.
18. The isolated HRS polypeptide of claim 15 , further comprising a heterologous fusion partner.
19. The isolated HRS polypeptide of claim 16 , where the heterologous fusion partner comprises a polyhistidine-tag.
20. The isolated HRS polypeptide of claim 16 , where the heterologous fusion partner comprises an Fc fragment.
21. The isolated HRS polypeptide of claim 1 , where the HRS polypeptide is modified by pegylation.
22. The isolated HRS polypeptide of claim 10 , where the HRS polypeptide is modified by pegylation.
23. The isolated HRS polypeptide of claim 15 , where the HRS polypeptide is modified by pegylation.
24. The isolated HRS polypeptide of claim 1 , where the HRS polypeptide comprises at least one chemical or enzymatic derivation at one or more constituent amino acids, where the at least one chemical or enzymatic derivation is selected from acetylation, hydroxylation, methylation, amidation, glycosylation, and lipidation.
25. The isolated HRS polypeptide of claim 10 , where the HRS polypeptide comprises at least one chemical or enzymatic derivation at one or more constituent amino acids, where the at least one chemical or enzymatic derivation is selected from acetylation, hydroxylation, methylation, amidation, glycosylation, and lipidation.
26. The isolated HRS polypeptide of claim 15 , where the HRS polypeptide comprises at least one chemical or enzymatic derivation at one or more constituent amino acids, where the at least one chemical or enzymatic derivation is selected from acetylation, hydroxylation, methylation, amidation, glycosylation, and lipidation.
27. An isolated recombinant histidyl-tRNA synthetase (HRS) polypeptide, for use in a method of reducing inflammatory activity wherein the HRS polypeptide is 50-175 amino acids in length and comprises at least 50 contiguous amino acids of SEQ ID NO: 6, or a variant thereof having at least 95% sequence identity to SEQ ID NO: 6, where the HRS polypeptide comprises a WHEP domain and lacks a functional aminoacylation domain.
28. The isolated HRS polypeptide of claim 27 , further comprising a heterologous fusion partner.
29. The isolated HRS polypeptide of claim 28 , where the heterologous fusion partner comprises a polyhistidine-tag.
30. The isolated HRS polypeptide of claim 28 , where the heterologous fusion partner comprises an Fc fragment.
31. The isolated HRS polypeptide of claim 27 , where the HRS polypeptide is modified by pegylation.
32. A pharmaceutical composition comprising a physiologically acceptable carrier and the HRS polypeptide of claim 1 .
33. A pharmaceutical composition comprising a physiologically acceptable carrier and the HRS polypeptide of claim 10 .
34. A pharmaceutical composition comprising a physiologically acceptable carrier and the HRS polypeptide of claim 15 .
35. A pharmaceutical composition comprising a physiologically acceptable carrier and the HRS polypeptide of claim 27 .
36. A pharmaceutical composition of claim 32 , where the composition is formulated with histidine.
37. A pharmaceutical composition of claim 33 , where the composition is formulated with histidine.
38. A pharmaceutical composition of claim 34 , where the composition is formulated with histidine.
39. A pharmaceutical composition of claim 35 , where the composition is formulated with histidine.