TREM2 plays a critical role in the alleviation of Alzheimer’s disease by promoting Aβ phagocytosis by microglia, but the detailed molecular mechanism underlying TREM2-induced direct phagocytic activity of Aβ remains to be revealed. We found that learning and memory functions were improved in aged TREM2 TG mice, with the opposite effects in KO mice. The amount of phagocytosed Aβ was significantly reduced in the primary microglia of KO mice. CD36 expression in primary microglia was greater in TG than in WT mice but was substantially decreased in KO mice. The expression of C/EBPα, an upstream transcriptional activator of CD36, was also elevated in primary microglia of TG mice but decreased in KO mice. The transcription of CD36 was markedly increased by TREM2 overexpression, and this effect was suppressed by a mutation of the C/EBPα binding site on the CD36 promoter. The TREM2-induced expression of CD36 and C/EBPα was inhibited by treatment with PI3K/AKT signaling blockers, and phosphorylation of AKT was elevated in TREM2-overexpressing BV2 cells. The present study provides evidence that TREM2 is required for preventing loss of memory and learning in Alzheimer’s disease by regulating C/EBPα-dependent CD36 expression and the consequent Aβ phagocytosis.

BiP and other endoplasmic reticulum (ER)-resident proteins are thought to be metabolically stable and to function primarily in the ER lumen. We sought to assess how the abundance of these proteins dynamically fluctuates in response to various stresses and how their subpopulations are relocated to non-ER compartments such as the cytosol. We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway. ER stress elicited the formation of R-BiP, an effect that was increased when the proteasome was also inhibited. Nt-arginylation correlated with the cytosolic relocalization of BiP under the types of stress tested. The cytosolic relocalization of BiP did not require the functionality of the unfolded protein response or the Sec61- or Derlin1-containing translocon. A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation. Pharmacological inhibition of the ER-Golgi secretory pathway also suppressed R-BiP formation. Finally, we showed that cytosolic R-BiP induced by ER stress and proteasomal inhibition was routed to autophagic vacuoles and possibly additional metabolic fates. These results suggest that Nt-arginylation is a posttranslational modification that modulates the function, localization, and metabolic fate of ER-resident proteins.

TREM2 (triggering receptor expressed on myeloid cells) is involved in the development of malignancies. However, the function of TREM2 in colorectal cancer has not been clearly elucidated. Here, we investigated TREM2 function for the first time in colorectal epithelial cancer cells and demonstrated that TREM2 is a novel tumor suppressor in colorectal carcinoma. Blockade of TREM2 significantly promoted the proliferation of HT29 colorectal carcinoma cells by regulating cell cycle-related factors, such as p53 phosphorylation and p21 and cyclin D1 protein levels. HT29 cell migration was also increased by TREM2 inhibition via MMP9 (matrix metalloproteinase 9) expression upregulation. Furthermore, we found that the tumor suppressor effects of TREM2 were associated with Wnt/β-catenin and extracellular signal-regulated kinase (ERK) signaling. Importantly, the effect of TREM2 in the suppression of tumor development was demonstrated by in vivo and in vitro assays, as well as in human colon cancer patient tissue arrays. Overall, our results identify TREM2 as a potential prognostic biomarker and therapeutic target for colorectal cancer.

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Recent advances in the field of nanoscience have enabled the preparation of high‐surface‐area supported catalysts with precise control over the individual structural components. As such, a range of factors that affect the catalytic reactivity, such as the size, shape, and composition of the nanoparticles (NPs), have been identified. Herein, high‐surface‐area model catalysts that were based on colloidal Pd NPs and a hexagonally ordered mesoporous carbon support were prepared and the impact of various organic capping agents for the Pd NPs on their catalytic activity towards Suzuki coupling reactions was investigated. Colloidal Pd NPs (diameter: 3 nm) were synthesized with different organic capping agents, oleylamine (OA) and trioctylphosphine (TOP), and they were subsequently incorporated into the mesopores of CMK‐3 mesoporous carbon to yield OA‐Pd/CMK‐3 and TOP‐Pd/CMK‐3 nanocatalysts, respectively. The OA‐Pd/CMK‐3 catalyst was treated with acetic acid to generate a supported catalyst with surfactant‐free Pd NPs (OA‐Pd/CMK‐3‐A). Structural characterization revealed that the Pd NPs were uniformly dispersed throughout the mesopores of the CMK‐3 support and the particle size and crystallinity of the Pd NPs were preserved following the incorporation. All of the Pd/CMK‐3 nanocatalysts exhibited higher activity than commercial activated carbon supported Pd catalysts in Suzuki coupling reactions. The catalytic activities of the three Pd/CMK‐3 nanocatalysts were in the following order: OA‐Pd/CMK‐3‐A>OA‐Pd/CMK‐3>TOP‐Pd/CMK‐3. This result suggested that the presence and type of surfactants had a significant effect on the catalytic activity. The OA‐Pd/CMK‐3‐A catalyst also showed high activity for various substrates and good recycling ability in Suzuki coupling reactions.