The E3 Ubiquitin Ligase MARCH8 Regulates TNF-α-Induced Apoptosis in Hippocampal Neurons by Targeting Myosin Light Chain 2 for Degradation.

Tumor necrosis factor-α (TNF-α) is an important inflammatory cytokine that plays a key role in neuronal damage. Elevated expression of TNF-α is associated with numerous neurodegenerative diseases including Alzheimer's Disease and Parkinson's Disease. However, the specific mechanism of the signaling events that trigger TNF-α-mediated neurotoxicity remain unknown. In this study, we report that intracerebroventricular injection of TNF-α in rat hippocampal neurons down-regulates MLC2 and up-regulates MARCH8, an essential light chain and regulatory myosin light chain of NM Myosin II, respectively. MARCH8 overexpression attenuates the degradation of MLC2 by promoting its ubiquitination and degradation. Inhibition of MARCH8 by siRNA blocks caspase-3 activation and apoptosis signaling, suggesting that TNF-α-induced apoptosis of neurons is partially dependent on the accumulation of MARCH8 and the ubiquitination of MLC2. Taken together, our data not only clarify the function of MARCH8 in TNF-α-induced neurotoxicity, but also demonstrates that TNF-α promotes the MARCH8-MLC2 mediated apoptosis of hippocampal neurons. Anat Rec, 302:2271-2278, 2019.