Technical Report
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Open Access
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News & Views |
Navigating ferroptosis via an NADPH sensor
NADPH levels serve as a biomarker of sensitivity to ferroptosis, but the regulators that detect cellular NADPH levels and modulate downstream ferroptosis responses are unknown. A study now identifies MARCHF6 in the ubiquitin system as an NADPH sensor that suppresses ferroptosis.
- Chao Mao
- & Boyi Gan
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Article |
The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis
Nguyen et al. show that the E3 ubiquitin ligase MARCHF6 acts as an NADPH sensor to suppress ferroptosis. Mechanistically, NADPH binds to MARCHF6 and activates its E3 ligase activity, enhancing the degradation of pro-ferroptosis proteins.
- Kha The Nguyen
- , Sang-Hyeon Mun
- & Cheol-Sang Hwang
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Article |
Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis
Moro et al. show that hypermethylation-induced silencing of the ubiquitin ligase FBXL7 rescues c-SRC from ubiquitin-mediated degradation and enhances epithelial-to-mesenchymal transition and metastasis.
- Loredana Moro
- , Daniele Simoneschi
- & Michele Pagano
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News & Views |
piRNA-unbound PIWIL1 promotes metastasis
Piwi proteins are aberrantly induced in human tumours, but their function in cancer has been poorly understood. A study now shows that in the absence of piRNA loading, human PIWIL1 promotes pancreatic cancer metastasis by acting as a co-activator of the anaphase-promoting complex/cyclosome (APC/C) to degrade the cell-adhesion protein Pinin.
- Fan Yao
- & Li Ma
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News & Views |
Parkin inhibits necroptosis to prevent cancer
Loss-of-function mutations in the ubiquitin ligase Parkin are a cause of Parkinson’s disease. Parkin also has tumour-suppressor activity, although how Parkin prevents cancer is unclear. Unexpectedly, Parkin is found to suppress cancer by inhibiting an inflammatory type of cell death called necroptosis.
- Kai Cao
- & Stephen W. G. Tait
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Article |
The AMPK–Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome
AMPK and Parkin keep the necrosome in check. Lee et al. show that AMPK activates Parkin and prevents RIPK1−RIPK3 complex formation by promoting RIPK3 ubiquitination, thereby negatively regulating necroptosis, inflammation and tumour initiation.
- Seung Baek Lee
- , Jung Jin Kim
- & Zhenkun Lou
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Correspondence |
Reply to ‘Dissecting the role of miR-140 and its host gene’
- Weiguo Zou
- , Rui Shao
- & Dallas Jones
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Correspondence |
Dissecting the roles of miR-140 and its host gene
- Masafumi Inui
- , Sho Mokuda
- & Hiroshi Asahara
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Article |
Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2
Choi et al. find that KLHL6, which is mutated in diffuse large B-cell lymphoma, is part of a ubiquitin ligase complex that targets the mRNA decay factor roquin2 for degradation and that loss of KLHL6 enhances cell survival through loss of TNFAIP3.
- Jaewoo Choi
- , Kyutae Lee
- & Luca Busino
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Article |
The mTOR–S6K pathway links growth signalling to DNA damage response by targeting RNF168
Xie and colleagues find that activated mTORC1 growth signalling impairs DNA repair through S6K-mediated phosphorylation and inhibition of the RNF168 ligase.
- Xiaoduo Xie
- , Hongli Hu
- & Daming Gao
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Article |
The TDH–GCN5L1–Fbxo15–KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells
Donato et al. show that Fbxo15 targets acetylated KBP for degradation to limit mitochondrial expansion, whereas KBP accumulation promotes mitochondrial biogenesis in a Kif1Bα-dependent manner.
- Valerio Donato
- , Massimo Bonora
- & Michele Pagano
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Letter |
Godzilla-dependent transcytosis promotes Wingless signalling in Drosophila wing imaginal discs
Vincent and colleagues show in Drosophila wing imaginal discs that the signalling molecule Wingless is synthesized and secreted at the apical surface, and is re-internalized to be transcytosed basally, where its signalling occurs.
- Yasuo Yamazaki
- , Lucy Palmer
- & Jean-Paul Vincent
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Article |
IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation
Through a proteomics approach, Qi and colleagues and Long and colleagues identify the sensor of the unfolded protein response IRE1α as an endogenous substrate of the E3 ubiquitin ligase involved in ER-associated degradation, Hrd1.
- Shengyi Sun
- , Guojun Shi
- & Ling Qi
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Article |
FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification
Aifantis and colleagues report that FBXW7α controls the heat-shock response pathway by targeting HSF1 for degradation. In melanoma FBXW7α deficiency leads to increased nuclear HSF1, and induction of a pro-invasive gene expression program.
- Nikos Kourtis
- , Rana S. Moubarak
- & Iannis Aifantis
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Article |
USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria
Cunningham et al. characterize the ubiquitin chain linkages regulated by the opposing activities of the E3 ligase parkin and the deubiquitylation enzyme USP30 on mitochondria.
- Christian N. Cunningham
- , Joshua M. Baughman
- & Jacob E. Corn
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Article |
SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma
The mTORC1 complex promotes protein translation and cell growth, whereas mTORC2 promotes survival. The Tel2 and Tt1 proteins belong to both complexes. Bassermann and colleagues demonstrate that following growth-factor deprivation, casein kinase 2 mediates phosphorylation of Tel2 and Tt1, specifically in the mTORC1 complex, to target them for degradation by the SCFFbxo9 ubiquitin ligase. This mechanism inactivates mTORC1 and activates mTORC2 and Akt signalling to promote survival of multiple myeloma cells.
- Vanesa Fernández-Sáiz
- , Bianca-Sabrina Targosz
- & Florian Bassermann
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Letter |
The SCF–FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication
The PLK4 kinase and centrosomal protein HsSAS-6 both regulate centrosome duplication. PLK4 negatively controls an FBXW5-containing ubiquitin ligase, which targets SAS-6 for destruction to restrict centrosome re-duplication.
- Anja Puklowski
- , Yahya Homsi
- & Nisar P. Malek
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Letter |
A tetrapyrrole-regulated ubiquitin ligase controls algal nuclear DNA replication
Organelle DNA replication is coupled to nuclear DNA replication in plant cells. In the red alga Cyanidioschyzon merolae, a plastid signalling molecule, Mg-ProtoIX, binds the F-box SCF ubiquitin ligase Fbx3 to inhibit cyclin 1 degradation and thus block nuclear DNA replication.
- Yuki Kobayashi
- , Sousuke Imamura
- & Kan Tanaka
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News & Views |
Working on a chain: E3s ganging up for ubiquitylation
Substrate specificity in ubiquitylation is conferred by ubiquitin ligases (E3s). Now, several ways that E3s can interact to mediate ubiquitylation are illustrated for Ubr1 (a RING finger E3) and Ufd4 (a HECT domain E3), in Saccharomyces cerevisiae. These interactions and the related concept of E4 activity are discussed.
- Meredith B. Metzger
- & Allan M. Weissman
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Article |
Interplay between Cdh1 and JNK activity during the cell cycle
The stress-activated kinase, JNK, is regulated by the anaphase promoting complex (APC) ubiquitin ligase. Conversely, JNK also negatively controls the APC by directly phosphorylating the Cdh1 component of the APC and decreasing its affinity for the APC core subunits.
- Gustavo J. Gutierrez
- , Toshiya Tsuji
- & Ze'ev A. Ronai
Defining E3 ligase–substrate relationships through multiplex CRISPR screening