Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36.

Ligand-induced epidermal growth factor receptor (EGFR) endocytosis followed by endosomal EGFR signaling and lysosomal degradation plays important roles in controlling multiple biological processes. ADP-ribosylation factor (Arf)-like protein 4 A (Arl4A) functions at the plasma membrane to mediate cytoskeletal remodeling and cell migration, whereas its localization at endosomal compartments remains functionally unknown. Here, we report that Arl4A attenuates EGFR degradation by binding to the endosomal sorting complex required for transport (ESCRT)-II component VPS36. Arl4A plays a role in prolonging the duration of EGFR ubiquitinylation and deterring endocytosed EGFR transport from endosomes to lysosomes under EGF stimulation. Mechanistically, the Arl4A-VPS36 direct interaction stabilizes VPS36 and ESCRT-III association, affecting subsequent recruitment of deubiquitinating-enzyme USP8 by CHMP2A. Impaired Arl4A-VPS36 interaction enhances EGFR degradation and clearance of EGFR ubiquitinylation. Together, we discover that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.

Combination therapy of sorafenib and drug-eluting bead transarterial chemoembolization for advanced hepatocellular carcinoma with and without hepatic arteriovenous shunt.

BACKGROUND: To compare the efficacy and safety of combination therapy with sorafenib and drug-eluting bead transarterial chemoembolization (DEB-TACE) in advanced hepatocellular carcinoma (HCC) with or without hepatic arteriovenous shunt (HAVS). METHODS: This retrospective, single-center study enrolled 59 advanced HCC patients treated with combination therapy, of whom 33 (55.9%) patients had HAVS. Tumor response according to the mRECIST criteria was evaluated based on the CT images 1 month after TACE, and changes in the arterial enhancement ratio (AER) of tumors and portal vein tumor thrombosis were also documented. Time-to-progression (TTP), overall survival (OS), and prognostic factors were analyzed. Safety was evaluated with the incidence of TACE-related complications within 6 weeks after TACE. RESULTS: The tumor response between the two groups showed no significant difference in the objective response rate (69.2% in the group without HAVS vs 60.6% in the group with HAVS, p = 0.492) or disease control rate (92.3% vs 87.9%, p = 0.685). The two groups showed comparable TTP (4.23 vs 2.33 months, p = 0.235) and OS (12.77 vs 12.97 months, p = 0.910). A drop in the AER of tumors of more than 20% on post-TACE CT independently predicted better OS. With regard to safety, there was no significant difference between the two groups. CONCLUSION: For advanced HCC, combination therapy had equal efficacy and safety in patients with HAVS compared to those without HAVS, indicating that DEB-TACE is an optional and effective treatment in these patients.

Healthy Intestinal Function Relies on Coordinated Enteric Nervous System, Immune System, and Epithelium Responses.

During both health and disease, a coordinated response between the epithelium, immune system, and enteric nervous system is required for proper intestinal function. While each system responds to a number of common stimuli, their coordinated responses support digestion as well as responses and recovery following injury or pathogenic infections. In this review, we discuss how individual responses to common signals work together to support these critical functions.

Zika Virus Infects Intermediate Progenitor Cells and Post-mitotic Committed Neurons in Human Fetal Brain Tissues.

Zika virus (ZIKV) infection is associated with microcephaly in fetuses, but the pathogenesis of ZIKV-related microcephaly is not well understood. Here we show that ZIKV infects the subventricular zone in human fetal brain tissues and that the tissue tropism broadens with the progression of gestation. Our research demonstrates also that intermediate progenitor cells (IPCs) are the main target cells for ZIKV. Post-mitotic committed neurons become susceptible to ZIKV infection as well at later stages of gestation. Furthermore, activation of microglial cells, DNA fragmentation, and apoptosis of infected or uninfected cells could be found in ZIKV-infected brain tissues. Our studies identify IPCs as the main target cells for ZIKV. They also suggest that immune activation after ZIKV infection may play an important role in the pathogenesis of ZIKV-related microcephaly.

Δ20 IFITM2 differentially restricts X4 and R5 HIV-1.

CCR5 (R5)-tropic, but not CXCR4 (X4)-tropic, HIV-1 is associated with primary HIV-1 infection and transmission. Recent studies have shown that IFN-induced transmembrane (IFITM) proteins, including IFITM1, IFITM2, and IFITM3, restrict a broad range of viruses. Here, we demonstrate that an IFITM2 isoform (Δ20 IFITM2) lacking 20 amino acids at the N terminus differentially restricts X4 and R5 HIV-1. Δ20 IFITM2 suppresses replication of X4 HIV-1 strains by inhibiting their entry. High levels of Δ20 IFITM2 expression could be detected in CD4+ T cells and in monocytes. Infection of X4 viruses in monocyte-derived macrophages and dendritic cells is enhanced upon depletion of IFITM2 isoforms. Furthermore, we also show that coreceptor use is the determining factor for differential HIV-1 restriction of Δ20 IFITM2. When we replace the C terminus of CCR5 with the C terminus of CXCR4, R5 viruses become more susceptible to Δ20 IFITM2-mediated restriction. In contrast to previous studies, our research reveals that neither X4 nor R5 HIV-1 is suppressed by IFITM2 and IFITM3. The multifactor gatekeeping model has been proposed to explain restriction of X4 viruses in the early stage of HIV-1 diseases. Our findings indicate that Δ20 IFITM2 may serve as a major contributor to this gatekeeping mechanism.