Combination treatment with metformin and tacrolimus improves systemic immune cellular homeostasis by modulating Treg and Th17 imbalance

Recycling and supply of plasma membrane (PM), referred to as PM turnover, are essential for maintaining integrity of neurons undergoing continuous dynamic morphological changes. Yet, the link of PM turnover to neuronal pathophysiology remains largely elusive. Here we showed that a subset of toxic polyglutamine proteins markedly compromised local targeting-recycling of PM components, reflecting a unique feature of early neuropathies. Such disruption of PM turnover in dendrites was ascribed primarily to alterations in dendritic endosomes and Golgi outposts accounting for local PM recycling and supply, respectively. Genome-wide mRNA-sequencing analysis identified CREB3L1/CrebA-COPII pathway to be responsible for the disruption of PM turnover. Indeed, CrebA overexpression reversed PM turnover impairment caused by these toxic proteins through restoring COPII pathway. Thus we demonstrate how PM turnover is linked to aberration of neuronal integrity in pathological conditions as well as its near-complete restoration through genetic engineering of CREB3L1/CrebA-COPII pathway. mRNA expression profiles of spleen CD4+ cells by Illumina NovaSeq 6000.