The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90

Abstract

Act1 is an essential adaptor molecule in IL-17-mediated signaling and is recruited to the IL-17 receptor upon IL-17 stimulation. Here, we report that Act1 is a client protein of the molecular chaperone, Hsp90. The Act1 variant (D10N) linked to psoriasis susceptibility is defective in its interaction with Hsp90, resulting in a global loss of Act1 function. Act1-/- mice modeled the mechanistic link between Act1 loss of function and psoriasis susceptibility. Although Act1 is necessary for IL-17-mediated inflammation, Act1-/- mice exhibited a hyper TH17 response and developed spontaneous IL-22-dependent skin inflammation. In the absence of IL-17-signaling, IL-22 is the main contributor to skin inflammation, providing a molecular mechanism for the association of Act1 (D10N) with psoriasis susceptibility.

Th17 Differentiation and Their Pro-inflammation Function

“…More importantly, deficiency of HuR in epithelium resulted in impaired IL-17A-mediated inflammation in lung, agreeing with the essential role of Act1 in epithelium of lung [96]. More recently, upon IL-17A exposure, heat shock protein 90 (Hsp90) was found to be associated with Act1 and this interaction was critical for the binding of Act1 with other signaling molecules [285]. Inhibitors of Hsp90 prevented the signaling complex formation and in turn inhibited the activation of downstream signaling pathways [285].…”

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…42 In addition to TRAF molecules, the study also showed that Act1 was associated with heat-shock protein 90 (hsp90) after IL-17 stimulation; this association was critical for IL-17-mediated signal activation. 43 Interestingly, the Act1 mutant D10N, which is associated with psoriasis, cannot bind to hsp90 and fails to initiate IL-17-induced downstream signaling. 43 In addition to the SEFIR domain, other studies have shown that the C-terminal region and 'TIR-like loop' (TILL) structure of IL-17RA, the cytosol tail region of IL-17RC, and the N-terminal domain of Act1 are critical for IL-17 signaling.…”

“…43 Interestingly, the Act1 mutant D10N, which is associated with psoriasis, cannot bind to hsp90 and fails to initiate IL-17-induced downstream signaling. 43 In addition to the SEFIR domain, other studies have shown that the C-terminal region and 'TIR-like loop' (TILL) structure of IL-17RA, the cytosol tail region of IL-17RC, and the N-terminal domain of Act1 are critical for IL-17 signaling. 9 A recent study showed that IL-17 activated the NF-κB pathway by down regulating microRNA-23b (miR-23b) to release its suppression on TAB2 and TAB3 expression.…”

Interleukin-17 cytokine signalling in patients with asthma

“…PARK et al [70] recently demonstrated that there is an association of single nucleotide polymorphisms on the IL-17RA gene and aspirine hypersensitivity in patients with asthma, thereby suggesting a pathogenic involvement of IL-17RA. Moreover, it was recently demonstrated that Act1 is a client protein of ATPase and the chaperone protein heat shock protein (Hsp)90 in an animal in vivo model of psoriasis [71]. When the Act1-Hsp90 interaction is disrupted, Th17 signalling through IL-17A becomes attenuated and the corresponding signalling through IL-22 becomes hyperresponsive.…”

“…When the Act1-Hsp90 interaction is disrupted, Th17 signalling through IL-17A becomes attenuated and the corresponding signalling through IL-22 becomes hyperresponsive. Given the high mammalian conservation of IL-17A-related mechanisms, it can be speculated that a malfunction in the critical interaction between Act1 and Hsp90 contributes to altered IL-17 signalling in human pathology, such as in asthma [71].…”