Custom Phospho-USP8 (Ser718) Antibody Reveals AKT–MDA5 Axis in Autoimmune Disease

Based on: Zhang Q et al., Advanced Science, 2025;12(34):e03865 — DOI: 10.1002/advs.202503865

MDA5 Aberrant Activation and Autoimmune Diseases

Melanoma Differentiation-Associated protein 5 (MDA5) is a cytoplasmic RNA sensor that 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 available. While deubiquitinases play crucial roles in immune signal regulation, the specific deubiquitinase governing MDA5 homeostasis had not been defined.

Core Finding: The AKT–USP8–MDA5 Regulatory Axis

Published in Advanced Science, this study identifies ubiquitin-specific protease 8 (USP8) as the core deubiquitinase regulating MDA5 homeostasis. The authors demonstrate that AKT directly phosphorylates USP8 at Ser718, enhancing USP8 activity and strengthening its association with MDA5 to form the AKT–USP8–MDA5 regulatory axis. In preclinical models, 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.

Molecular Pathway Under Viral Infection

AtaGenix’s Role: Custom Phospho-Specific Antibody

AtaGenix developed a custom phospho-specific antibody against human USP8 Ser718 for this study. The antibody specifically recognizes the Ser718-phosphorylated form of USP8, enabling accurate detection of USP8 phosphorylation dynamics upon viral infection or AKT pathway activation. It served as a critical experimental 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 of USP8 Ser718 phosphorylation using the AtaGenix-produced custom phospho-specific antibody. Adapted from Zhang et al., Adv Sci 2025.

Confirmed Therapeutic Potential

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 and systemic lupus erythematosus (SLE) patient cells, supporting USP8/AKT as a promising therapeutic direction for MDA5-associated autoimmune diseases.

Key Metrics

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

Results may vary depending on target, antibody design, and project scope. All proprietary client information is subject to NDA.