Endoplasmic reticulum associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity

SummaryMany tissue-specific stem cells require quiescence to sustain stem cell pool and maintain lifelong tissue integrity. It remains unclear whether protein quality control is required for stem cells in quiescence when RNA content, protein synthesis and metabolic activities are significantly reduced. Here, we report that endoplasmic reticulum associated degradation (ERAD) is required to preserve the function of quiescent hematopoietic stem cells (HSC). The Sel1L/Hrd1 ERAD genes are enriched in the quiescent and inactive HSCs, and conditional knockout of Sel1L in hematopoietic tissues drives HSCs to hyper-proliferation which leads to reduced self-renewal and HSC depletion. ERAD deficiency induces a non-apoptotic ER stress and activates unfolded protein response (UPR). Furthermore, Sel1L knockout leads to mTOR activation, and mTOR inhibition rescues the HSC defects in Sel1L knockout mice. Protein quality control is, therefore, tightly regulated and actively engaged in quiescent HSCs. Sel1L/Hrd1 ERAD maintains HSC quiescence and self-renewal via restricting mTOR activity.

Hypothalamic ER–associated degradation regulates POMC maturation, feeding, and age-associated obesity

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

A CRISPR-Based Screen Identifies Genes Essential for West-Nile-Virus-Induced Cell Death

Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling

Recent reports have highlighted the roles of free fatty acid receptor 2 (FFAR2) in the regulation of metabolic and inflammatory processes. However, the potential function of FFAR2 in type 1 diabetes (T1D) remains unexplored. Our results indicated that the mRNA level of FFAR2 was upregulated in peripheral blood mononuclear cells of T1D patients. The human FFAR2 promoter regions were cloned, and luciferase reporter assays revealed that NFκB activation induced FFAR2 expression. Furthermore, we showed that FFAR2 activation by overexpression induced cell apoptosis through ERK signaling. Finally, treatment with the FFAR2 agonists acetate or phenylacetamide 1 attenuated the inflammatory response in multiple-low-dose streptozocin-induced diabetic mice, and improved the impaired glucose tolerance. These results indicate that FFAR2 may play a protective role by inducing apoptosis of infiltrated macrophage in the pancreas through its feedback upregulation and activation, thus, in turn, improving glucose homeostasis in diabetic mice. These findings highlight FFAR2 as a potential therapeutic target of T1D, representing a link between immune response and glucose homeostasis.

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

TAB2, an important upstream adaptor of interleukin-1 signaling pathway, is subject to SUMOylation

Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice

Caenorhabditis elegans mom-4 is required for the activation of the p38 MAPK signaling pathway in the response to Pseudomonas aeruginosa infection

Inhibitory effect of Andrographolide in 3T3-L1 adipocytes differentiation through the PPARγ pathway

Glucocorticoids Promote Hepatic Cholestasis in Mice by Inhibiting the Transcriptional Activity of the Farnesoid X Receptor

Protective effect of andrographolide against concanavalin A-induced liver injury

Andrographolide attenuates tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes

Selection of reference genes for quantitative real-time reverse transcription-polymerase chain reaction in concanavalin A-induced hepatitis model

An Essential Role for RIG-I in Toll-like Receptor-Stimulated Phagocytosis