TY  - JOUR
A1  - Kalie, Eyal
A1  - Jaitin, Diego A.
A1  - Podoplelova, Yulia
A1  - Piehler, Jacob
A1  - Schreiber, Gideon
T1  - The stability of the ternary interferon-receptor complex rather than the affinity to the individual subunits dictates differential biological activities
T2  - Journal of biological chemistry
N2  - Type I interferons (IFNs) signal for their diverse biological effects by binding a common receptor on target cells, composed of the two transmembrane IFNAR1 and IFNAR2 proteins. We have previously differentially enhanced the antiproliferative activity of IFN by increasing the weak binding affinity of IFN to IFNAR1. In this study, we further explored the affinity interdependencies between the two receptor subunits and the role of IFNAR1 in differential IFN activity. For this purpose, we generated a panel of mutations targeting the IFNAR2 binding site on the background of the IFNalpha2 YNS mutant, which increases the affinity to IFNAR1 by 60-fold, resulting in IFNAR2-to-IFNAR1 binding affinity ratios ranging from 1000:1 to 1:1000. Both the antiproliferative and antiviral potencies of the interferon mutants clearly correlated to the in situ binding IC(50) values, independently of the relative contributions of the individual receptors, thus relating to the integral lifetime of the complex. However, the antiproliferative potency correlated throughout the entire range of affinities, as well as with prolonged IFNAR1 receptor down-regulation, whereas the antiviral potency reached a maximum at binding affinities equivalent to that of wild-type IFNalpha2. Our data suggest that (i) the specific activity of interferon is related to the ternary complex binding affinity and not to affinity toward individual receptor components and (ii) although the antiviral pathway is strongly dependent on pSTAT1 activity, the cytostatic effect requires additional mechanisms that may involve IFNAR1 down-regulation. This differential interferon response is ultimately mediated through distinct gene expression profiling.
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/76362
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-763621
SN  - 0021-9258
VL  - 283.2008
IS  - 47
SP  - 32925
EP  - 32936
PB  - American Society for Biochemistry and Molecular Biology Publications
CY  - Bethesda, Md
ER  -