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RNF213

Domain

Composed of an N-terminal stalk, a dynein-like core comprised of two catalytically active and four inactive ATPase domains, and a C-terminal E3 module. The ATPase regions do not generate movement but rather act like an intricate molecular 'switch'.

The RING-type zinc finger domain is required for the ubiquitin-protein ligase activity.

The RZ-type (RNF213-ZNFX1) zinc-finger is required for the ubiquitination of the lipid A moiety of bacterial lipopolysaccharide (LPS).

Function

Atypical E3 ubiquitin ligase that can catalyze ubiquitination of both proteins and lipids, and which is involved in various processes, such as lipid metabolism, angiogenesis and cell-autonomous immunity (PubMed:21799892, PubMed:26126547, PubMed:26278786, PubMed:26766444, PubMed:30705059, PubMed:32139119, PubMed:34012115). Acts as a key immune sensor by catalyzing ubiquitination of the lipid A moiety of bacterial lipopolysaccharide (LPS) via its RZ-type zinc-finger: restricts the proliferation of cytosolic bacteria, such as Salmonella, by generating the bacterial ubiquitin coat through the ubiquitination of LPS (PubMed:34012115). Also acts indirectly by mediating the recruitment of the LUBAC complex, which conjugates linear polyubiquitin chains (PubMed:34012115). Ubiquitination of LPS triggers cell-autonomous immunity, such as antibacterial autophagy, leading to degradation of the microbial invader (PubMed:34012115). Involved in lipid metabolism by regulating fat storage and lipid droplet formation; act by inhibiting the lipolytic process (PubMed:30705059). Also regulates lipotoxicity by inhibiting desaturation of fatty acids (PubMed:30846318). Also acts as an E3 ubiquitin-protein ligase via its RING-type zinc finger: mediates 'Lys-63'-linked ubiquitination of target proteins (PubMed:32139119, PubMed:33842849). Involved in the non-canonical Wnt signaling pathway in vascular development: acts by mediating ubiquitination and degradation of FLNA and NFATC2 downstream of RSPO3, leading to inhibit the non-canonical Wnt signaling pathway and promoting vessel regression (PubMed:26766444). Also has ATPase activity; ATPase activity is required for ubiquitination of LPS (PubMed:34012115).

Involvement in disease

Moyamoya disease 2

MYMY2

A progressive cerebral angiopathy characterized by bilateral intracranial carotid artery stenosis and telangiectatic vessels in the region of the basal ganglia. The abnormal vessels resemble a 'puff of smoke' (moyamoya) on cerebral angiogram. Affected individuals can develop transient ischemic attacks and/or cerebral infarction, and rupture of the collateral vessels can cause intracranial hemorrhage. Hemiplegia of sudden onset and epileptic seizures constitute the prevailing presentation in childhood, while subarachnoid bleeding occurs more frequently in adults.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

A chromosomal aberration involving RNF213 is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALK.

Pathway

Protein modification; protein ubiquitination.

Post-translational modifications

Autoubiquitinated.

Sequence Similarities

Belongs to the AAA ATPase family.

Tissue Specificity

Widely expressed (at protein level).

Isoform 1

Major isoform detected in all tissues examined.

Isoform 2

Minor isoform with restricted expression.

Cellular localization

Alternative names

ALO17, C17orf27, KIAA1554, KIAA1618, MYSTR, RNF213, E3 ubiquitin-protein ligase RNF213, ALK lymphoma oligomerization partner on chromosome 17, E3 ubiquitin-lipopolysaccharide ligase RNF213, Mysterin, RING finger protein 213

swissprot:Q63HN8 omim:613768 swissprot:Q9HCF4 entrezGene:57674