Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and reroutes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.(F) IF co-staining of distal tubule in MKD patient kidney organoid for MUC1-wt (red), MUC1-fs (green), E-cadherin (blue), and Na + /K + -ATPase (yellow). MUC1-fs localized intracellularly (middle) compared to apical MUC1-wt (left). (G) IF co-staining in P cells for MUC1-fs (green), MUC1-wt (red), and Hoechst (gray). MUC1-fs localized intracellularly (middle) compared to MUC1-wt on the plasma membrane (left). See also Figures S1, S2, and S3 and Table S1.

Highlights d Tim-1 + B cells are required for maintaining immune tolerance d Tim-1 + B cells differentially express TIGIT and other coinhibitory molecules d B cell expression of TIGIT and many other regulators requires Tim-1 signaling d B cell TIGIT expression is preferentially required for maintaining CNS tolerance

Protein arginine methyltransferases (PRMTs) catalyze symmetric and asymmetric methylation on arginine residues of multiple protein targets including histones and have essential roles in organismal development and disease. PRMT5 mediates symmetric di-methylation (sDMA) of arginine 2 (H3R2me2s) and arginine 8 on histone 3 (H3R8me2s), arginine 3 on histones 2A and 4 (H2A/H4R3me2s) as well as several non-histone substrates like Sm proteins. Here, we found that selective inhibition of PRMT5 in mesenchymal stromal cells (MSCs) led to a reduction in colony forming units (CFUs) and increased osteoblast differentiation. PRMT5 inhibition blocked global symmetric dimethylation of H3R8 and H4R3 but not on H3R2. Genome-wide expression analysis by total RNA sequencing of mesenchymal stromal cells undergoing osteogenic differentiation revealed significant reduction in the intrinsic expression of several interferon-stimulated genes (ISGs) upon PRMT5 inhibition. Effects of PRMT5 inhibition on basal ISG expression and osteogenic differentiation was effectively blocked by exogenous activation of type I IFN signaling. Together, these results indicate important functions for PRMT5 in the regulation of basal interferon gene expression in MSCs and in the control of differentiation potential of MSCs during osteogenic differentiation.