Endoplasmic reticulum-associated degradation (ERAD) and beyond: the multitasking roles for Hrd1 in immune regulation, inflammation and metabolic regulation.
The current dogma underlying peripheral T cell tolerance is that TCRs on self-reactive T cells, upon recognition of self-antigens without CD28 co-stimulation induce the expression of genes that suppress the activation of self-reactive T cells (known as anergic genes, such as Sirt1). Similar to a vehicle that can be slowed down by either tightening a break or shutting off the gas, we posited that, in addition to upregulating the suppressive genes, anergic signaling may down-regulate certain activators (positive regulators) of T cells to induce and maintain peripheral tolerance. The novel hypothesis led to our identification of Hrd1, an ER resident ubiquitin ligase critical for ERAD, as one of the down-regulated factors for T cell tolerance induction (Nature Communications, 2016). On the other hand, Hrd1 protects inflammation-induced Treg instability through suppressing IRE1 activation (JCI insight, 2018). Hrd1 also protects B cells from activation induced apoptosis through targeting the death receptor Fas for degradation (PNAS, 2016). Moreover, Hrd1 controls the optimal MHC-II expression in dendritic cells for promoting CD4 T cell priming during inflammation (Journal of Experimental Medicine, 2014). In addition to immune regulation, Hrd1 programs liver metabolism by targeting multiple metabolic enzymes (Nature Communications, 2018). More interestingly, we demonstrated that liver Hrd1 bridges a multi-organ crosstalk in regulating growth, circadian behavior, and female fertility (EMBO Journal, 2018). Our laboratory is further investigating the multitasking roles of Hrd1-ERAD in immune regulation, inflammation and cancer.