Single cell dissociation antibody staining and FACS sorting Cellular atlas DEGs Cellular interaction Ligand Recepto r Immunostaining Functional assays Correlation analysis Droplet-based scRNA-seq Data Cell 1 Cell 2 Cell x Gene 1 Gene 2 Gene y Highlights Single cell transcriptomic datasets are a valuable resource to dissect cellular diversity and intercellular crosstalk of human ICCs. Malignant cells displayed remarkable inter-tumor heterogeneity and Tregs revealed highly immunosuppressive characteristics. Six distinct fibroblast subsets were defined in ICCs and adjacent tissues. CD146 + vCAFs, comprising most of the fibroblasts, had tight interactions with malignant cells through IL-6/IL-6R axis. Tumor exosomal miR-9-5p elicited IL-6 expression in vCAFs, contributing to ICC progression via upregulation of EZH2.

Mutations in Parkin, an E3 ubiquitin ligase that regulates protein turnover, represent one of the major causes of familial Parkinson disease, a neurodegenerative disorder characterized by the loss of dopaminergic neurons and impaired mitochondrial functions. The underlying mechanism by which pathogenic Parkin mutations induce mitochondrial abnormality is not fully understood. Here, we demonstrate that Parkin interacts with and subsequently ubiquitinates dynamin-related protein 1 (Drp1), for promoting its proteasome-dependent degradation. Pathogenic mutation or knockdown of Parkin inhibits the ubiquitination and degradation of Drp1, leading to an increased level of Drp1 for mitochondrial fragmentation. These results identify Drp1 as a novel substrate of Parkin and suggest a potential mechanism linking abnormal Parkin expression to mitochondrial dysfunction in the pathogenesis of Parkinson disease. Parkinson disease (PD)4 is one of the most common neurodegenerative diseases affecting over 2% populations over 65 years of age. It is classically characterized by the loss of dopaminergic neurons that project from the midbrain substantia nigra to the striatum (1, 2). Although the loss of dopaminergic neurons is responsible for the symptom of movement disorder in PD, it is now clear that other types of neurons throughout the brain are also affected in the disease (3, 4). The identification of genes linking to PD has greatly advanced our understanding of the molecular pathogenesis of the disease (5-8). Mutations in Parkin represent one of major causes for early onset of familial PD (9 -11). Parkin is an E3 ubiquitin ligase that contains two ring finger domains (12-15). A handful of substrates have been identified, including Parkin itself and CDCrel-1, synphilin-1, Pael-R, glycosylated ␣-synuclein, FBP1 (far upstream elementbinding protein 1), and the RNA-processing protein subunit p38/AIMP2 (16 -19). A putative mechanism by which mutations of Parkin cause PD would be abnormal accumulation and aggregation of the above substrates due to insufficient E3 ligase activity for ubiquitin-proteasome-dependent protein turnover (18,20,21). Surprisingly, only p38/AIMP2 and FBP1 were found to be accumulated in the brain samples of PD patients or in Parkin knock-out mice (16,17,19). Even though a number of the putative substrates have been identified, the causative link between these substrates and the PD pathogenesis remains not fully understood.Over the past few decades, accumulating evidence has suggested that mitochondrial dysfunction and the resulting oxidative damage are associated with PD. This is supported by a large number of reports demonstrating impaired mitochondrial functions in PD patients (22)(23)(24)(25)(26). Mitochondria undergo frequent fission, fusion, and redistribution throughout the cytoplasm in response to the energy needs (27,28). Either disruption of the fusion process or enhancement of the fission process renders the normal, tubular network of mitochondria to fragment into short rods or spheres (29). Abnormal...

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