SUMOylation of GMFB regulates the stability and function of GMFB in RPE cells under oxidative stress and inflammation

Abstract

Glia maturation factor beta (GMFB) is a growth and differentiation factor that act as an intracellular regulator of signal transduction pathways. The SUMOylation is a post-translational modification (PTM) that plays a key role in protein subcellular localization, stability, transcription, and enzymatic activity. Recent studies have highlighted the importance of SUMOylation in the inflammation and progression of numerous diseases. But little is known about the relationship between GMFB and SUMOylation. Here we first report that GMF can be mono-SUMOylated at multiple sites by the covalent addition of a single SUMO1 protein, and identified K20, K35, K58, and K97 as major SUMO acceptor sites. We also found that SUMOylation leading to increased stability and trans-localization of GMF. Furthermore, RNA-seq data and Real-time quantitative polymerase chain reaction (rt-qPCR) also indicated that the SUMOylated GMF upregulated multiple pathways, including the cytokine-cytokin receptor interaction, NOD-like receptor signaling pathway, TNF signaling pathway, RIG-I-like receptor signaling pathway, and NF-kappa B signaling pathway. Our studies intend to provide a novel direction for the study into the biofunction of GMFB, SUMOylated GMFB and the mechanism, clinical therapy, and prognosis of inflammation-related RPE disorders like age-related macular degeneration (AMD) and diabetic retinopathy (DR).

G9a Inhibition Promotes Neuroprotection through GMFB Regulation in Alzheimer’s Disease

“…As aforementioned, G9a can also methylate non-histone proteins [ 96 ]. Furthermore, recently it has been proposed a novel direction for the study of GMFB biofunction after being SUMOylated at multiple sites by SUMO1 [ 23 ]. But nothing has been described about the link between GMFB and methylation.…”

“…It is a highly evolutionarily conserved protein and is expressed in a wide range of animals [ 22 ], including invertebrates [ 21 ]. Interestingly, GMFB participates in several inflammatory and immune conditions [ 23 ]. As mentioned above, PTMs play a crucial role in almost all biological processes [ 23 ], and one example is the SUMOylation, which has been considered to play a role in inflammatory processes [ 24 ].…”

“…Interestingly, GMFB participates in several inflammatory and immune conditions [ 23 ]. As mentioned above, PTMs play a crucial role in almost all biological processes [ 23 ], and one example is the SUMOylation, which has been considered to play a role in inflammatory processes [ 24 ]. A recent study reported that GMFΒ can be mono-SUMOylated at multiple site by covalent addition of a single SUMO1 protein, fostering the stability and trans-localization of GMFB [ 23 ].…”

“…As mentioned above, PTMs play a crucial role in almost all biological processes [ 23 ], and one example is the SUMOylation, which has been considered to play a role in inflammatory processes [ 24 ]. A recent study reported that GMFΒ can be mono-SUMOylated at multiple site by covalent addition of a single SUMO1 protein, fostering the stability and trans-localization of GMFB [ 23 ]. Another important clue is that GMFB is implicated in the regulation of neuronal and glial growth and differentiation [ 25 - 27 ].…”

“…Of note, G9a and GMFB are associated with neuroinflammation, increasing pro-inflammatory cytokines. Likewise, they are known to play a key role in several neurodegenerative diseases [ 29 , 30 ], and participate in neuronal plasticity, among other degenerative pathways [ 23 , 31 , 32 ]. However, neither the transcriptional regulation of GMFB by G9a nor the G9a-mediated methylation of GMFB have been described.…”