Mechanism of USP8 Regulating MDA5 Homeostasis and Its Therapeutic Potential in Autoimmune Diseases

MDA5 Aberrant Activation and Autoimmune Diseases - Key Bottleneck in Mechanistic Research

Melanoma Differentiation-Associated protein 5 (MDA5), a cytoplasmic RNA sensor, initiates type I interferon signaling against RNA viruses. However, its aberrant activation (via viral infection or gain-of-function mutations) can drive autoimmune diseases such as Aicardi–Goutières syndrome (AGS) and anti-MDA5-positive dermatomyositis (DM), with limited effective treatments in many settings. Deubiquitinases play crucial roles in immune signal regulation, but the deubiquitinase governing MDA5 homeostasis had not been clearly defined.

Core Finding in Advanced Science - Identification of the AKT-USP8-MDA5 Regulatory Axis

Featured in Advanced Science, this study reports a key breakthrough by identifying ubiquitin-specific protease 8 (USP8) as a core deubiquitinase regulating MDA5 homeostasis. The authors further show that AKT directly phosphorylates USP8 at Ser718, a modification that enhances USP8 activity and strengthens its association with MDA5, forming the AKT-USP8-MDA5 regulatory axis. In the preclinical models described in the study, inhibiting USP8 or AKT promotes degradation of pathogenic MDA5 and dampens excessive immune signaling, supporting this axis as a potential therapeutic entry point for MDA5-associated autoimmune diseases.

Signal Transduction Under Viral Infection - Molecular Pathway of USP8 Regulating MDA5

1. Viral infection activates AKT, which phosphorylates USP8 at Ser718, strengthening the interaction between USP8 and MDA5;
2. USP8 stabilizes MDA5 by deubiquitinating it, promoting type I interferon production;
3. Inhibiting USP8 or AKT facilitates degradation of both wild-type and mutant MDA5, blocking excessive immune signaling.

Antibody Customized by AtaGenix - Core Experimental Tool for Mechanism Validation

A phospho-specific antibody against human USP8 Ser718 was customized by AtaGenix. This customized antibody specifically recognizes the Ser718-phosphorylated form of USP8, enabling accurate detection of USP8 phosphorylation dynamics upon viral infection or AKT pathway activation. It serves as a practical tool to verify the regulatory effect of AKT on USP8 and to assess the activation status of the signaling axis in mechanism-focused studies.

Fig. 1: Detection results of phospho-antibody

Confirmed Therapeutic Potential - Clinical Value of USP8/AKT as Novel Targets

USP8 is a critical regulator of MDA5 homeostasis, and the AKT-USP8 axis helps balance innate immunity and autoimmunity. In the study’s preclinical models, inhibiting USP8 or AKT effectively suppresses MDA5-induced autoimmunity in AGS mice and reduces excessive immune signaling in anti-MDA5-positive DM/systemic lupus erythematosus (SLE) patient cells, supporting USP8/AKT as a promising therapeutic direction for MDA5-associated autoimmune diseases.

References

1) Zhang Q, Huang S, He Y, Wang W, Tong C, Ma M, Zhao M, Yi L, Knobeloch K-P, Zhang P. USP8-Governed MDA5 Homeostasis Promotes Innate Immunity and Autoimmunity. Advanced Science. 2025;12(34):e03865. DOI: 10.1002/advs.202503865.