The AAA+ ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets

Sugihara, Munechika; Morito, Daisuke; Ainuki, Shiori; Hirano, Yoshinobu; Ogino, Kazutoyo; Kitamura, Akira; Hirata, Hiromi; Nagata, Kazuhiro

doi:10.1083/jcb.201712120

Cited by 103 publications

(105 citation statements)

References 26 publications

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“…Previous studies showed that RNF213 oligomerizes via its ATPase domain (Morito et al, 2014) and has ubiquitin ligase activity (Banh et al, 2016;Kobayashi et al, 2015). ATPase activity also has been implicated in recruitment to, and stabilization of, lipid droplets (Sugihara et al, 2019). However, the type of UB linkages added by RNF213, the cooperating E2(s), and the role(s) of the AAA-ATPase and E3 domains in MMD pathogenesis have remained unknown or controversial.…”

Section: Discussionmentioning

confidence: 99%

“…Studies of larger panels of RNF213 alleles will be required to solidify these findings. A recent study suggested that RNF213 localizes to and stabilizes lipid droplets (Sugihara et al, 2019). Furthermore, RNF213 also stabilizes the droplets by removing ATGL (a lipase).…”

Section: Discussionmentioning

confidence: 99%

“…Different RNF213 SNPs are associated with variable penetrance of MMD (Cecchi et al, 2014;Guey et al, 2017;Kamada et al, 2011;Liu et al, 2011;Sugihara et al, 2019). To explore the role of RNF213 E3 ligase activity on MMD, we assessed the E3 ligase activity associated with SNPs of different penetrance (Fig.…”

Section: Mmd-associated Snps Encode Mutants With Decreased E3 Activitmentioning

confidence: 99%

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Moyamoya Disease-AssociatedRNF213Alleles Encode Dominant Negative Alleles That Globally Impair Ubiquitylation

Bhardwaj

Banh

Zhang

et al. 2020

Preprint

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Single nucleotide polymorphisms (SNPs) in RNF213, which encodes a 591kDa protein with AAA+ ATPase and RING E3 domains, are associated with a rare, autosomal dominant cerebrovascular disorder, Moyamoya disease (MMD). MMD-associated SNPs primarily localize to the C-terminal region of RNF213, and some affect conserved residues in the RING domain.Although the autosomal dominant inheritance of MMD could most easily be explained by RNF213 gain-of-function, the type of ubiquitylation catalyzed by RNF213 and the effects of MMDassociated SNPs on its E3-ligase activity have remained unclear. We found that the RING domain of RNF213 uses the E2-conjugating enzyme UBE2D2 to catalyze predominantly K6-dependent poly-ubiquitination events comprising a mixture of typical and atypical ubiquitin linkages. MMDassociated SNPs encode proteins with decreased E3-ligase activity and the most frequent MMD allele, RNF213 R4810K , is a dominant negative mutant that decreases ubiquitylation globally. By contrast, MMD-associated RNF213 SNPs do not affect ATPase activity. We propose that decreased RNF213 E3-ligase activity is central to MMD pathogenesis.the RNF213 R4810K allele (Cecchi et al., 2014;Moteki et al., 2015). Several other rare RNF213 variants are found in MMD patients of diverse ethnicities (Cecchi et al., 2014;Kobayashi et al., 2016;Moteki et al., 2015). Although ~2% of Japanese individuals have RNF213 R4810K , the prevalence of MMD is low (~0.006%), indicating that additional genetic and/or environmental modifiers are required for pathogenesis (Ran et al., 2013).RNF213 encodes an ~591kDa protein containing tandem AAA+ ATPase domains and a RING E3 domain (Fig. 1a). The AAA+ ATPase domains mediate RNF213 oligomerization into a homo-hexamer (Morito et al., 2014). Nucleotide (ATP/ADP) binding to the first ATPase domain stabilizes the oligomer, and destabilization occurs upon ATP hydrolysis by the second domain.Less, however, is known about the RNF213 E3 domain. RING E3 domains catalyze UB (ubiquitin) transfer from (an) E2 ubiquitin-conjugating enzyme(s) to lysine residues of E3-bound substrate(s), resulting in isopeptide bond formation (Deshaies and Joazeiro, 2009). Mono-ubiquitylation joins a single UB molecule to a substrate, although multiple sites on the same substrate can be mono-ubiquitylated ("multi-monoubiquitylation"). Poly-ubiquitylation occurs when UB residues are added sequentially to a specific lysine residue in a previously conjugated UB, forming a UB chain. The N-terminal methionine and seven lysine residues (K6, K11, K27, K29, K33, K48 and K63) in UB can participate in polyubiquitylation, leading to linear and/or branched UB chains (Yau and Rape, 2016). Some E2s appear to promote specific types of UB linkages; others are more promiscuous. Most E3 ubiquitin ligases can interact with several E2s, thereby catalyzing production of different types of UB chains.Depending on the specific UB linkage, ubiquitylation regulates diverse cellular processes, including protein degradation, endocytic trafficking, inflammation, transl...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mmd-associated Snps Encode Mutants With Decreased E3 Activitmentioning

confidence: 99%

See 1 more Smart Citation

Moyamoya Disease-AssociatedRNF213Alleles Encode Dominant Negative Alleles That Globally Impair Ubiquitylation

Bhardwaj

Banh

Zhang

et al. 2020

Preprint

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“…Lastly, mysterin/RNF213 is a AAA ATPase with a ubiquitin ligase domain, which is implicated in signaling pathways involved in vascular development that supports cancer growth and metastasis (106,107). Interestingly, mysterin is also involved in the stabilization of lipid droplets, which are regulated by SEPT9 in cells that are infected by the hepatitis C virus (108,109).…”

Section: Functional Clustering Of the Sept9 Proteome Points To Isoformentioning

confidence: 99%

Proteomic profiling of the oncogenic septin 9 reveals isoform-specific interactions in breast cancer cells

Devlin

Perkins

Bowen

et al. 2019

Preprint

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Septins are a family of multimeric GTP-binding proteins, which are abnormally expressed in cancer. Septin 9 (SEPT9) is an essential and ubiquitously expressed septin with multiple isoforms, which have differential expression patterns and effects in breast cancer cells. It is unknown, however, if SEPT9 isoforms associate with different molecular networks and functions. Here, we performed a proteomic screen in MCF-7 breast cancer cells to identify the interactome of GFP-SEPT9 isoforms 1, 4 and 5, which vary significantly in their N-terminal extensions. While all three isoforms associated with SEPT2 and SEPT7, the truncated SEPT9_i4 and SEPT9_i5 interacted with septins of the SEPT6 group more promiscuously than SEPT9_i1, which bound predominately SEPT8. Spatial mapping and functional clustering of non-septin partners showed isoform-specific differences in interactions with proteins of distinct subcellular organelles (e.g., nuclei, centrosomes, cilia) and functions such as cell signaling and ubiquitination. Notably, the interactome of the full length SEPT9_i1 was more enriched in cytoskeletal regulators, while the truncated SEPT9_i4 and SEPT9_i5 exhibited preferential and isoform-specific interactions with nuclear, signaling and ubiquitinating proteins. These data provide evidence for isoform-specific interactions, which arise from truncations in the N-terminal extensions of SEPT9, and point to novel roles in the pathogenesis of breast cancer. L.D. performed experiments, analyzed data, made figures and co-wrote manuscript with E.T.S.; G.P. contributed technically and intellectually to ESI/LC-MS/MS experimentation and softwarebased peptide identification; J.R.B. performed microscopy imaging; C.M. created MCF-7 cell lines and contributed to the manuscript; E.T.S. conceived and directed the project (experiments and analyses), drafted manuscript and edited figures.

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“…Furthermore, how cells sense lipid peroxidation and mount an orchestrated multi-organelle response to maintain lipid homeostasis remains poorly understood, but is likely critical to our understanding of many diseases. Indeed, new work continues to reveal disease-related proteins like Rab18, Snx14, and Mysterin that play unexpected but important roles in lipid metabolism and LD crosstalk with other organelles (13–15), but how these proteins work together to connect LDs with other cellular compartments requires further study.…”

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confidence: 99%