Smooth Muscle Cell-Macrophage Interactions Leading to Foam Cell Formation in Atherosclerosis: Location, Location, Location.

Cholesterol-overloaded cells or "foam cells" in the artery wall are the biochemical hallmark of atherosclerosis, and are responsible for much of the growth, inflammation and susceptibility to rupture of atherosclerotic lesions. While it has previously been thought that macrophages are the main contributor to the foam cell population, recent evidence indicates arterial smooth muscle cells (SMCs) are the source of the majority of foam cells in both human and murine atherosclerosis. This review outlines the timeline, site of appearance and proximity of SMCs and macrophages with lipids in human and mouse atherosclerosis, and likely interactions between SMCs and macrophages that promote foam cell formation and removal by both cell types. An understanding of these SMC-macrophage interactions in foam cell formation and regression is expected to provide new therapeutic targets to reduce the burden of atherosclerosis for the prevention of coronary heart disease, stroke and peripheral vascular disease.

SNAP47 Interacts with ATG14 to Promote VP1 Conjugation and CVB3 Propagation.

Coxsackievirus B3 (CVB3), an enterovirus (EV) in the family of Picornaviridae, is a global human pathogen for which effective antiviral treatments and vaccines are lacking. Previous research demonstrated that EV-D68 downregulated the membrane fusion protein SNAP47 (synaptosome associated protein 47) and SNAP47 promoted EV-D68 replication via regulating autophagy. In the current study, we investigated the interplay between CVB3 and cellular SNAP47 using HEK293T/HeLa cell models. We showed that, upon CVB3 infection, protein levels of SNAP47 decreased independent of the activity of virus-encoded proteinase 3C. We further demonstrated that the depletion of SNAP47 inhibited CVB3 infection, indicating a pro-viral function of SNAP47. Moreover, we found that SNAP47 co-localizes with the autophagy-related protein ATG14 on the cellular membrane fractions together with viral capsid protein VP1, and expression of SNAP47 or ATG14 enhanced VP1 conjugation. Finally, we revealed that disulfide interactions had an important role in strengthening VP1 conjugation. Collectively, our study elucidated a mechanism by which SNAP47 and ATG14 promoted CVB3 propagation through facilitating viral capsid assembly.

Coxsackievirus infection induces a non-canonical autophagy independent of the ULK and PI3K complexes.

Coxsackievirus B3 (CVB3) is a single-stranded positive RNA virus that usurps cellular machinery, including the evolutionarily anti-viral autophagy pathway, for productive infections. Despite the emergence of double-membraned autophagosome-like vesicles during CVB3 infection, very little is known about the mechanism of autophagy initiation. In this study, we investigated the role of established autophagy factors in the initiation of CVB3-induced autophagy. Using siRNA-mediated gene-silencing and CRISPR-Cas9-based gene-editing in culture cells, we discovered that CVB3 bypasses the ULK1/2 and PI3K complexes to trigger autophagy. Moreover, we found that CVB3-induced LC3 lipidation occurred independent of WIPI2 and the transmembrane protein ATG9 but required components of the late-stage ubiquitin-like ATG conjugation system including ATG5 and ATG16L1. Remarkably, we showed the canonical autophagy factor ULK1 was cleaved through the catalytic activity of the viral proteinase 3C. Mutagenesis experiments identified the cleavage site of ULK1 after Q524, which separates its N-terminal kinase domain from C-terminal substrate binding domain. Finally, we uncovered PI4KIIIß (a PI4P kinase), but not PI3P or PI5P kinases as requisites for CVB3-induced LC3 lipidation. Taken together, our studies reveal that CVB3 initiates a non-canonical form of autophagy that bypasses ULK1/2 and PI3K signaling pathways to ultimately converge on PI4KIIIß- and ATG5-ATG12-ATG16L1 machinery.

Dysregulation of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis.

Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have revealed a strong association between mutations in genes encoding many RNA-binding proteins (RBPs), including TARDBP, FUS, hnRNPA1, hnRNPA2B1, MATR3, ATXN2, TAF15, TIA-1, and EWSR1, and disease onset/progression. RBPs are a group of evolutionally conserved proteins that participate in multiple steps of RNA metabolism, including splicing, polyadenylation, mRNA stability, localization, and translation. Dysregulation of RBPs, as a consequence of gene mutations, impaired nucleocytoplasmic trafficking, posttranslational modification (PTM), aggregation, and sequestration by abnormal RNA foci, has been shown to be involved in neurodegeneration and the development of ALS. While the exact mechanism by which dysregulated RBPs contribute to ALS remains elusive, emerging evidence supports the notion that both a loss of function and/or a gain of toxic function of these ALS-linked RBPs play a significant role in disease pathogenesis through facilitating abnormal protein interaction, causing aberrant RNA metabolism, and by disturbing ribonucleoprotein granule dynamics and phase transition. In this review article, we summarize the current knowledge on the molecular mechanism by which RBPs are dysregulated and the influence of defective RBPs on cellular homeostasis during the development of ALS. The strategies of ongoing clinical trials targeting RBPs and/or relevant processes are also discussed in the present review.