Assembly-dependent Structure Formation Shapes Human Interleukin-23 versus Interleukin-12 Secretion.
J Mol Biol
; 435(23): 168300, 2023 12 01.
Article
in En
| MEDLINE
| ID: mdl-37805067
ABSTRACT
Interleukin 12 (IL-12) family cytokines connect the innate and adaptive branches of the immune system and regulate immune responses. A unique characteristic of this family is that each member is anαßheterodimer. For human αsubunits it has been shown that they depend on theirßsubunit for structure formation and secretion from cells. Since subunits are shared within the family and IL-12 as well as IL-23 use the same ßsubunit, subunit competition may influence cytokine secretion and thus downstream immunological functions. Here, we rationally design a folding-competent human IL-23α subunit that does not depend on itsßsubunit for structure formation. This engineered variant still forms a functional heterodimeric cytokine but shows less chaperone dependency and stronger affinity in assembly with its ßsubunit. It forms IL-23 more efficiently than its natural counterpart, skewing the balance of IL-12 and IL-23 towards more IL-23 formation. Together, our study shows that folding-competent human IL-12 familyαsubunits are obtainable by only few mutations and compatible with assembly and function of the cytokine. These findings might suggest that human α subunits have evolved for assembly-dependent folding to maintain and regulate correct IL-12 family member ratios in the light of subunit competition.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interleukin-12
/
Interleukin-23
/
Protein Multimerization
Limits:
Humans
Language:
En
Journal:
J Mol Biol
Year:
2023
Document type:
Article
Affiliation country:
Germany