Disrupting PIAS3-mediated SUMOylation of MLK3 ameliorates poststroke neuronal damage and deficits in cognitive and sensorimotor behaviors

• DOI: 10.1007/s00018-024-05166-7
• Publication Date: 2024-03-08T06:29:26Z
• Authors: Yu Jiang; Lulu Hu; Baixue Wang; Bingge Zhang; Mengwen Shao; Li Meng; Yan Xu; Rourou Chen; Meng Li; Caiping Du
• Keywords: ASK1; Protein kinase R; Neurite; Cyclin-dependent kinase 9

Abstract Activated small ubiquitin-like modifiers (SUMOs) have been implicated in neuropathological processes following ischemic stroke. However, the target proteins of SUMOylation and their contribution to neuronal injury remain be elucidated. MLK3 (mixed-lineage kinase 3), a member mitogen-activated protein (MAPKKK) family, is critical regulator lesions cerebral ischemia. Here, we found that increases both global focal rodent models primary oxygen glucose deprivation (OGD). SUMO1 conjugation at Lys401 site promoted its activation, stimulated downstream p38/c-Jun N-terminal (JNK) cascades, led cell apoptosis. The interaction with PIAS3, SUMO ligase, was elevated ischemia reperfusion. PINIT domain PIAS3 involved direct interactions MLK3. Overexpression disrupted MLK3-PIAS3 interaction, inhibited MLK3, suppressed signaling, reduced apoptosis neurite damage. In models, overexpression brain alleviated deficits learning, memory, sensorimotor functions. Our findings demonstrate ischemia-induced by potential against poststroke behavioral impairments.