Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome

Structures of the interleukin 11 signalling complex reveal dynamics of gp130 extracellular domains and the inhibitory mechanism of a cytokine variant

“…This analysis shows that the D4-D6 region of gp130 is dynamic and is not stabilised upon complex formation. The proposed flexibility of D4-D6 is in agreement with our ITC results showing that the gp130EC complex forms with similar affinity to the gp130D1-D3 complex, and is supported by our previous molecular dynamics (MD) simulations of gp130 D2-D5 showing that D4 is dynamic with respect to D3 63 . Together these data indicate that D4-D6 of gp130 do not contribute to complex formation.…”

“…In future, this knowledge may inform how these pathways are co-activated, or individually activated in disease, as evidence emerges that there may be a cell context dependent IL-11 mediated activation of STAT3 pro-survival pathways compared to IL-11 mediated ERK driven proliferation and apoptosis in disease 69 . Importantly, by defining the structural and biophysical dynamics of gp130 within the signalling complex our data enable a better understanding of the pathogenicity of emerging cytokine selective variants in IL6ST 63,[70][71][72][73][74][75] , as well as variants in IL11R 76,77 and IL11 78,79 , for which there are no targeted therapeutic opportunities for patients.…”

Structural insights into the assembly of gp130 family cytokine signaling complexes

“…Three point mutations, N404Y, P498L, and A517P, were identified at the gp130 D3-D4, D4-D5, and D5-D6 interfaces, respectively. While these mutations all significantly inhibited IL-6 and IL-11 signaling and resulted in partial-to-severe reduction of CNTF, CLCF1, IL-27, OSM, and CT-1 signaling, they barely or only partially impair LIF signaling ( 45 – 47 ). All-atom molecular dynamics simulations of the three gp130 variants suggested increased conformational flexibility at both the D3-D4 interface caused by the N404Y mutation and the D5-D6 interface due to the A517P mutation, and more subtle effect of the P498L mutation on the dynamics of the D4-D5 interface, consistent with the observation that the P498L variant showed more subtle defectiveness in pSTAT3 response compared with the other two variants ( 45 ).…”

Human autoantibodies underlying infectious diseases

“…The description of dominant-negative mutations of STAT3 as the main cause of AD HIES ( Asano et al, 2021b ; Minegishi et al, 2007 ) revealed that impaired STAT3-dependent signaling downstream from several cytokines, including IL-6 ( Kane et al, 2014 ), caused the complex clinical and cellular phenotype observed in these patients characterized by severe early-onset atopic dermatitis, recurrent skin and sino-pulmonary bacterial infections, CMC, poor or delayed clinical and biological signs of inflammation, eosinophilia, high serum IgE levels, low levels of memory B and Th17 cells, and various nonhematopoietic features ( Tsilifis et al, 2021 ). Following this discovery, additional IEI associated with most, if not all of the clinical features observed in classical HIES, were reported, including AR deficiency of ZNF341, a transcription factor governing STAT3 expression and activity ( Beziat et al, 2018 ; Frey-Jakobs et al, 2018 ), and partial AR ( Chen et al, 2021b ; Schwerd et al, 2017 ; Shahin et al, 2019 ) or AD ( Beziat et al, 2020 ) deficiencies of GP130, the signaling receptor subunit common to all IL-6 family cytokines ( Rose-John, 2018 ), suggesting that impaired IL-6 immunity underlies many of the key immunological and clinical features of HIES. Patients with AR IL-6R deficiency were first reported in 2019 ( Nahum et al, 2020 ; Spencer et al, 2019 ).…”