ER-phagy restrains inflammatory responses through its receptor UBAC2.

ER-phagy, a selective form of autophagic degradation of endoplasmic reticulum (ER) fragments, plays an essential role in governing ER homeostasis. Dysregulation of ER-phagy is associated with the unfolded protein response (UPR), which is a major clue for evoking inflammatory diseases. However, the molecular mechanism underpinning the connection between ER-phagy and disease remains poorly defined. Here, we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy, while at the same time being a negative regulator of inflammatory responses. UBAC2 harbors a canonical LC3-interacting region (LIR) in its cytoplasmic domain, which binds to autophagosomal GABARAP. Upon ER-stress or autophagy activation, microtubule affinity-regulating kinase 2 (MARK2) phosphorylates UBAC2 at serine (S) 223, promoting its dimerization. Dimerized UBAC2 interacts more strongly with GABARAP, thus facilitating selective degradation of the ER. Moreover, by affecting ER-phagy, UBAC2 restrains inflammatory responses and acute ulcerative colitis (UC) in mice. Our findings indicate that ER-phagy directed by a MARK2-UBAC2 axis may provide targets for the treatment of inflammatory disease.

Identification of necroptosis-related gene signatures for predicting the prognosis of ovarian cancer.

Ovarian cancer (OC) is one of the most prevalent and fatal malignant tumors of the female reproductive system. Our research aimed to develop a prognostic model to assist inclinical treatment decision-making.Utilizing data from The Cancer Genome Atlas (TCGA) and copy number variation (CNV) data from the University of California Santa Cruz (UCSC) database, we conducted analyses of differentially expressed genes (DEGs), gene function, and tumor microenvironment (TME) scores in various clusters of OC samples.Next, we classified participants into low-risk and high-risk groups based on the median risk score, thereby dividing both the training group and the entire group accordingly. Overall survival (OS) was significantly reduced in the high-risk group, and two independent prognostic factors were identified: age and risk score. Additionally, three genes-C-X-C Motif Chemokine Ligand 10 (CXCL10), RELB, and Caspase-3 (CASP3)-emerged as potential candidates for an independent prognostic signature with acceptable prognostic value. In Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, pathways related to immune responses and inflammatory cell chemotaxis were identified. Cellular experiments further validated the reliability and precision of our findings. In conclusion, necroptosis-related genes play critical roles in tumor immunity, and our model introduces a novel strategy for predicting the prognosis of OC patients.

Nickel-Catalyzed Amidoalkylation Reaction of γ-Hydroxy Lactams: An Access to 3-Substituted Isoindolinones.

An efficient Ni(ClO4)2·6H2O-promoted amidoalkylation reaction for the synthesis of 3-substituted isoindolinones involving various γ-hydroxy lactams and nucleophiles has been successfully developed. The transformation proceeds with both carbon (ketones and arenes) and heteroatom (alcohols, thiols, and amines) nucleophiles and in both intermolecular and intramolecular manners. The prominent features of the present strategy are wide substrate scope, excellent group tolerability, and moderate to good yields (up to 96% yield). The present strategy is also characterized by remarkable superiority over the current synthetic methods. Furthermore, the reaction could be scaled up to the multigram scale.