Highlights d Peripheral CD4 + T cells control stress-induced anxiety-like behavior d Mitochondrial fission in peripheral CD4 + T cell causes severe anxiety symptoms d T cell-derived xanthine acts on the oligodendrocytes in the left amygdala d IRF-1 controls purine synthesis in CD4 + T cells and triggers the onset of anxiety

The systemic RNAi-defective (SID) transmembrane family member 2 (SIDT2) is a putative nucleic acid channel or transporter that plays essential roles in nucleic acid transport and lipid metabolism. Here, we report the cryo-electron microscopy (EM) structures of human SIDT2, which forms a tightly packed dimer with extensive interactions mediated by two previously uncharacterized extracellular/luminal β-strand-rich domains and the unique transmembrane domain (TMD). The TMD of each SIDT2 protomer contains eleven transmembrane helices (TMs), and no discernible nucleic acid conduction pathway has been identified within the TMD, suggesting that it may act as a transporter. Intriguingly, TM3-6 and TM9-11 form a large cavity with a putative catalytic zinc atom coordinated by three conserved histidine residues and one aspartate residue lying approximately 6 Å from the extracellular/luminal surface of the membrane. Notably, SIDT2 can hydrolyze C18 ceramide into sphingosine and fatty acid with a slow rate. The information presented advances the understanding of the structure-function relationships in the SID1 family proteins.

The defects in storage proteins secretion in the endosperm of transgenic rice seeds often leads to endoplasmic reticulum (ER) stress, which produces floury and shrunken seeds, but the mechanism of this response remains unclear. We used an iTRAQ-based proteomics analysis of ER-stressed rice seeds due to the endosperm-specific suppression of OsSar1 to identify changes in the protein levels in response to ER stress. ER stress changed the expression of 405 proteins in rice seed by >2.0- fold compared with the wild-type control. Of these proteins, 140 were upregulated and 265 were downregulated. The upregulated proteins were mainly involved in protein modification, transport and degradation, and the downregulated proteins were mainly involved in metabolism and stress/defense responses. A KOBAS analysis revealed that protein-processing in the ER and degradation-related proteasome were the predominant upregulated pathways in the rice endosperm in response to ER stress. Trans-Golgi protein transport was also involved in the ER stress response. Combined with bioinformatic and molecular biology analyses, our proteomic data will facilitate our understanding of the systemic responses to ER stress in rice seeds.

Endoplasmic reticulum-associated protein degradation (ERAD) plays an important role in endoplasmic reticulum (ER) quality control. To date, little is known about the retrotranslocation machinery in the plant ERAD pathway. We obtained a DERLIN-like protein (OsDER1) through a SWATH-based quantitative proteomic analysis of ER membrane proteins extracted from ER-stressed rice () seeds. OsDER1, a homolog of yeast and mammal DER1, is localized in the ER and accumulates significantly under ER stress. Overexpression or suppression of OsDER1 in rice leads to activation of the unfolded protein response and hypersensitivity to ER stress, and suppression results in floury, shrunken seeds. In addition, the expression levels of polyubiquitinated proteins increased markedly in overexpression or suppression transgenic rice. Coimmunoprecipitation experiments demonstrated that OsDER1 interacted with OsHRD1, OsHRD3, and OsCDC48, the essential components of the canonical ERAD pathway. Furthermore, OsDER1 associated with the signal peptide peptidase, a homolog of a component of the alternative ERAD pathway identified recently in yeast and mammals. Our data suggest that OsDER1 is linked to the ERAD pathway.