“…Compared to the antiviral activity, the antibacterial effect of RNF213 was more pronounced and dependent on ISG15. These results show that RNF213 plays an important role in the innate cellular immune response against invading Listeria , which is in line with recent findings on Salmonella 65 and indicating a functional link between ISG15 and RNF213. Fig.…”
ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we use a virus-like particle trapping technology to identify ISG15-binding proteins and discover Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We report that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We show that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1, human respiratory syncytial virus and coxsackievirus B3, and we observe a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.
“…Compared to the antiviral activity, the antibacterial effect of RNF213 was more pronounced and dependent on ISG15. These results show that RNF213 plays an important role in the innate cellular immune response against invading Listeria , which is in line with recent findings on Salmonella 65 and indicating a functional link between ISG15 and RNF213. Fig.…”
ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we use a virus-like particle trapping technology to identify ISG15-binding proteins and discover Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We report that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We show that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1, human respiratory syncytial virus and coxsackievirus B3, and we observe a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.
“…This means that ATPase and E3 ligase work cooperatively. In fact, deletion or mutations of the ATPase domain reduced the function of E3 ligase ( 39 , 43 ) ( Figure 1 ). This may explain the reason why MMD is caused by both mutations in the ATPase and those in the E3 ligase.…”
Section: Molecular Structure and Functionsmentioning
confidence: 99%
“…Because Rift Valley fever virus infection suppresses the response of IFN-β or other IFN-related molecules ( 92 , 93 ), type-I IFN mediated upregulation of Rnf213 is not likely to be the mechanism of action against the virus. More recently, it has been shown that RNF213 restricts the proliferation of cytosolic Salmonella and is essential for the generation of the bacterial ubiquitin coat, which initiates antibacterial autophagy ( 43 ). The ubiquitylation of LPS on Salmonella requires the AAA+ ATPase domain and newly identified NFX1-type zinc finger domain (ZF2 in Figure 1 ).…”
Section: Functions Of Rnf213 and Sgc In Vascular Insultsmentioning
Moyamoya disease is an idiopathic chronically progressive cerebrovascular disease, which causes both ischemic and hemorrhagic stroke. Genetic studies identified RNF213/Mysterin and GUCY1A3 as disease-causing genes. They were also known to be associated with non-moyamoya intracranial large artery disease, coronary artery disease and pulmonary artery hypertension. This review focused on these two molecules and their strong linker, calcineurin/NFAT signaling and caveolin to understand the pathophysiology of moyamoya disease and related vascular diseases. They are important regulators of lipid metabolism especially lipotoxicity, NF-κB mediated inflammation, and nitric oxide-mediated vascular protection. Although intimal thickening with fibrosis and damaged vascular smooth muscle cells are the distinguishing features of moyamoya disease, origin of the fibrous tissue and the mechanism of smooth muscle cell damages remains not fully elucidated. Endothelial cells and smooth muscle cells have long been a focus of interest, but other vascular components such as immune cells and extracellular matrix also need to be investigated in future studies. Molecular research on moyamoya disease would give us a clue to understand the mechanism preserving vascular stability.
“…The crossovers between ubiquitylation and Atg8ylation exist, as glimpsed from emerging examples of ubiquitylation being able to occur on complex glycolipids such as bacterial LPS (lipopolysaccharide) when introduced into the mammalian cell [ 174 ], potentially blurring the borders of specialization between ubiquitylation and Atg8ylation relative to proteins vs. membranes. Conversely, two recent reports of protein Atg8ylation [ 175 , 176 ] confirm that Atg8ylation and ubiquitylation are more similar than previously appreciated, although the biological significance of protein Atg8ylation is yet to be explored.…”
The yeast Atg8 protein and its paralogs in mammals, mammalian Atg8s (mAtg8s), have been primarily appreciated for their participation in autophagy. However, lipidated mAtg8s, including the most frequently used autophagosomal membrane marker LC3B, are found on cellular membranes other than autophagosomes. Here we put forward a hypothesis that the lipidation of mAtg8s, termed ‘Atg8ylation’, is a general membrane stress and remodeling response analogous to the role that ubiquitylation plays in tagging proteins. Ubiquitin and mAtg8s are related in sequence and structure, and the lipidation of mAtg8s occurs on its C-terminal glycine, akin to the C-terminal glycine of ubiquitin. Conceptually, we propose that mAtg8s and Atg8ylation are to membranes what ubiquitin and ubiquitylation are to proteins, and that, like ubiquitylation, Atg8ylation has a multitude of downstream effector outputs, one of which is autophagy.
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