News & Views |
Featured
-
-
Technical Report
| Open Access
Defining E3 ligase–substrate relationships through multiplex CRISPR screening
Timms, Mena et al. present a multiplex CRISPR screening platform capable of assigning E3 ligases to their substrates and degrons at scale.
- Richard T. Timms
- , Elijah L. Mena
- & Stephen J. Elledge
-
Article |
Nuclear and cytoplasmic spatial protein quality control is coordinated by nuclear–vacuolar junctions and perinuclear ESCRT
Sontag et al. show that nuclear misfolded proteins and juxtanuclear cytoplasmic misfolded proteins converge to opposite sides of the nuclear envelope, proximal to nuclear–vacuolar junctions for ESCRT-dependent egress to the vacuole.
- Emily M. Sontag
- , Fabián Morales-Polanco
- & Judith Frydman
-
Article
| Open Access
Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7
Deshwal et al. show that the protease PARL regulates coenzyme Q (CoQ) via the lipid transfer protein STARD7. Mitochondrial STARD7 ensures CoQ synthesis; cytosolic STARD7 preserves CoQ transport to the membrane, protecting cells against ferroptosis.
- Soni Deshwal
- , Mashun Onishi
- & Thomas Langer
-
Article
| Open Access
ER-associated RNA silencing promotes ER quality control
Efstathiou et al. describe an Argonaute-dependent endoplasmic reticulum (ER)-associated RNA silencing pathway that acts together with ER-associated protein degradation to preserve ER homeostasis and function.
- Sotirios Efstathiou
- , Franziska Ottens
- & Thorsten Hoppe
-
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
-
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
-
Article
| Open Access
Actin remodelling controls proteasome homeostasis upon stress
Williams et al. report that, upon TORC1 inhibition in yeast, mRNA of the chaperone protein ADC17 is localized to cortical actin patches where its translation is enhanced upon stress.
- Thomas David Williams
- , Roberta Cacioppo
- & Adrien Rousseau
-
Article
| Open Access
CDK1–cyclin-B1-induced kindlin degradation drives focal adhesion disassembly at mitotic entry
Chen et al. report that at mitotic entry, cyclin B1–CDK1 phosphorylates the focal adhesion protein kindlin to induce its proteasomal degradation and promote focal adhesion disassembly and mitotic rounding.
- Nan-Peng Chen
- , Jonas Aretz
- & Reinhard Fässler
-
News & Views |
Centrosomes grow aggresomes to clear waste
Overload of proteasomal clearance triggers formation of a large protein inclusion called the aggresome, which shares similarities with protein aggregates seen in neurodegenerative diseases such as Huntington’s. A new study uncovers how centrosome and centriolar satellite components facilitate stepwise assembly of aggresomes.
- Elisa Vitiello
- & Fanni Gergely
-
Article
| Open Access
Aggresome assembly at the centrosome is driven by CP110–CEP97–CEP290 and centriolar satellites
Prosser et al. report that centriolar satellite and centrosomal proteins seed aggresomes, perinuclear inclusions of misfolded proteins, and may play a role in aggresome formation during senescence and huntingtin aggregation.
- Suzanna L. Prosser
- , Johnny Tkach
- & Laurence Pelletier
-
Article |
LONP-1 and ATFS-1 sustain deleterious heteroplasmy by promoting mtDNA replication in dysfunctional mitochondria
Yang et al. report that ATFS-1 preferentially accumulates in dysfunctional mitochondria carrying mutated mitochondria DNA (∆mtDNA) and facilitates mtDNA replication by promoting POLG recruitment, resulting in the replicative advantage of ∆mtDNA and heteroplasmy maintenance.
- Qiyuan Yang
- , Pengpeng Liu
- & Cole M. Haynes
-
News & Views |
Chaperone-mediated autophagy on the clock
Rhythmic removal of circadian clock proteins is important for the strength and periodicity of the circadian rhythm. A study now reveals that chaperone-mediated autophagy regulates the degradation of circadian proteins, and is also transcriptionally regulated by the circadian machinery. This feedback loop helps to maintain circadian oscillations.
- Congcong He
-
News & Views |
Surveying the mitochondrial proteome
Mitochondrial-derived vesicles (MDVs) transfer mitochondrial content to lysosomes and peroxisomes. A study now reveals that MDVs deliver β-barrel proteins and fully assembled mitochondrial complexes for lysosomal degradation, establishing an important role for MDVs in mitochondrial protein quality control.
- Dominic Winter
- & Thomas Becker
-
Article |
MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control
By characterizing the composition of mitochondrial-derived vesicles (MDVs), König et al. define a MIRO1/2- and DRP1-dependent MDV biogenesis pathway and propose that MDVs maintain the mitochondrial proteome by shuttling assembled protein complexes to lysosomes.
- Tim König
- , Hendrik Nolte
- & Heidi M. McBride
-
News & Views |
Mitochondrial UPR through generations
Neuronal mitochondria perturbation elicits a mitochondrial unfolded protein response (UPRmt) in peripheral tissues cell non-autonomously, dependent on the Wnt signalling pathway. A study now reveals that a Wnt-mediated increase in maternally inherited mitochondria DNA is responsible for transgenerational UPRmt induced by neuronal mitochondria perturbation.
- Mooncheol Park
- & Meng C. Wang
-
Article |
The memory of neuronal mitochondrial stress is inherited transgenerationally via elevated mitochondrial DNA levels
Zhang et al. report that the systemic mitochondrial unfolded protein response triggered by neuronal mitochondrial stress can be transmitted across multiple generations in Caenorhabditis elegans via a mechanism involving elevation in mitochondrial DNA levels in oocytes.
- Qian Zhang
- , Zihao Wang
- & Ye Tian
-
News & Views |
H19 lncRNA to dystrophin’s rescue
There are many challenges in finding an effective, long-lasting and universal cure for the whole cohort of patients with Duchenne muscular dystrophy (DMD). The discovery of H19 lncRNA as a stabiliser of dystrophin may prove to be the missing link to the success of various rescue therapies proposed for treating DMD.
- Morten Ritso
- & Michael A. Rudnicki
-
Article |
The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin
Zhang et al. report that the lncRNA H19 stabilizes dystrophin by competing with the ubiquitin E3 ligase TRIM63 for association with dystrophin, thereby alleviating muscular dystrophies.
- Yaohua Zhang
- , Yajuan Li
- & Liuqing Yang
-
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
-
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
-
Letter |
Selective autophagy degrades nuclear pore complexes
Lee et al. show that, after nitrogen starvation and genetic interference with the architecture of nuclear pore complexes, nucleoporins are degraded by autophagy, constituting a quality-control step at the nuclear envelope.
- Chia-Wei Lee
- , Florian Wilfling
- & Boris Pfander
-
News & Views |
PTEN isoforms with dual and opposing function
PTEN is a phosphatase that functions as a tumour suppressor by antagonizing the PI3K–AKT pathway. However, a study now demonstrates that translational variants of PTEN enable new interactions between PTEN and the COMPASS complex, identifying a new role for PTEN in modifying gene expression via COMPASS-mediated histone H3 lysine 4 methylation.
- Justin Taylor
- & Omar Abdel-Wahab
-
Article |
PTENα and PTENβ promote carcinogenesis through WDR5 and H3K4 trimethylation
Shen et al. show that PTENα/β stability is regulated through a ubiquitin-dependent mechanism mediated by USP9X and FBXW11 to modulate H3K4 trimethylation through WDR5 and promote tumour development.
- Shao-Ming Shen
- , Cheng Zhang
- & Guo-Qiang Chen
-
Article |
CaMKII-δ9 promotes cardiomyopathy through disrupting UBE2T-dependent DNA repair
Zhang et al. report the role of CaMKII-δ9, a previously less-studied isoform, in driving cardiomyopathy. Mechanistically, CaMKII-δ9 phosphorylates UBE2T, resulting in its degradation and impairing DNA repair.
- Mao Zhang
- , Hua Gao
- & Rui-Ping Xiao
-
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
-
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
-
Article |
A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain
Necroptosis drives arthritis. Polykratis et al. show that the deubiquitinating enzyme A20 inhibits inflammasome-dependent arthritis development by regulating macrophage necroptosis and this function depends on its ZnF7 ubiquitin binding domain.
- Apostolos Polykratis
- , Arne Martens
- & Manolis Pasparakis
-
Article |
Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme
Boos et al. show that impairing mitochondrial protein import induces a global transcriptional response to activate the ubiquitin–proteasome system and heat stress response and repress oxidative phosphorylation genes.
- Felix Boos
- , Lena Krämer
- & Johannes M. Herrmann
-
Article |
Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification
Şentürk et al. show that ubiquilins bind v-ATPase to control lysosome acidity, mTOR signalling and autophagic flux in neurons, and that feeding flies with acidic nanoparticles ameliorates defective autophagy in ubiquilin mutants.
- Mümine Şentürk
- , Guang Lin
- & Hugo J. Bellen
-
News & Views |
Protein quality and miRNA slicing get into phase
Phase separation can build assemblies and regulate biological function. Two articles link specific forms of protein and RNA degradation to phase separation. The polyubiquitin shuttle factor UBQLN2 localizes to stress granules where it may extract ubiquitinated proteins, and the miRISC complex functions through phase separation.
- Tanja Mittag
- & Nicolas L. Fawzi
-
Correspondence |
Reply to ‘Dissecting the role of miR-140 and its host gene’
- Weiguo Zou
- , Rui Shao
- & Dallas Jones
-
Correspondence |
Dissecting the roles of miR-140 and its host gene
- Masafumi Inui
- , Sho Mokuda
- & Hiroshi Asahara
-
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
-
-
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
-
News & Views |
Hitchhiking on selective autophagy
Selective autophagy is important for controlled degradation of cellular components. However, a selective autophagic degradation mechanism for ribosomes in mammals has remained unclear. A study now describes non-selective and selective ribosome degradation and a significant role for ‘bystander’ non-selective autophagy.
- Christian Münch
- & Ivan Dikic
-
Article |
The MTM1–UBQLN2–HSP complex mediates degradation of misfolded intermediate filaments in skeletal muscle
Gavriilidis et al. show that MTM1, which is mutated in X-linked centronuclear myopathy, and UBQLN2 recognize misfolded desmin and vimentin and trigger their degradation to clear misfolded intermediated filaments prior to aggregate formation.
- Christos Gavriilidis
- , Leila Laredj
- & Karim Hnia
-
News & Views |
PERK links the clock and protein stress in cancer
The unfolded protein response (UPR) regulates cell metabolism and survival in response to stress, yet how the UPR is connected to other signalling pathways is poorly understood. PERK is now shown to regulate Bmal1 and Clock proteins to promote cancer cell survival, revealing a link between growth regulation and circadian rhythms.
- Miguel Sanchez-Alvarez
- & Chris Bakal
-
Letter |
Systematic analysis of ribophagy in human cells reveals bystander flux during selective autophagy
An and Harper quantify ribophagy in mammalian cells and show that nutrient-deprivation-induced ribophagy is independent of the ATG8 conjugation system, whereas proteotoxic stress-induced ribophagy requires ATG5 and VPS34.
- Heeseon An
- & J. Wade Harper
-
Article |
A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival
PERK regulates tumour cell survival. Bu et al. show that the unfolded protein response protein PERK induces miR-211 repression of the circadian factor Bmal1 to regulate protein synthesis and stress responses, contributing to tumour progression.
- Yiwen Bu
- , Akihiro Yoshida
- & J. Alan Diehl
-
Article |
Pramel7 mediates ground-state pluripotency through proteasomal–epigenetic combined pathways
Graf et al. demonstrate that Pramel7 maintains ground-state pluripotency by repressing DNA methylation through proteasomal degradation of UHRF1, thus linking the proteasome and epigenetics with cell fate regulation.
- Urs Graf
- , Elisa A. Casanova
- & Paolo Cinelli
-
Article |
Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation
Wang et al. show that lipid-induced ROS lead to ACAT2 stabilization by oxidizing a cysteine residue, thereby preventing its ubiquitylation and ACAT2 degradation. They further show that ACAT2 stabilization improves lipotoxicity and insulin resistance.
- Yong-Jian Wang
- , Yan Bian
- & Bao-Liang Song
-
Letter |
Receptor oligomerization guides pathway choice between proteasomal and autophagic degradation
Lu et al. show that the choice between proteasomal degradation and selective autophagy is independent of the ubiquitin-binding properties of the receptors but largely determined by oligomerization potential.
- Kefeng Lu
- , Fabian den Brave
- & Stefan Jentsch
-
News & Views |
PARL paves the way to apoptosis
Although the mitochondrial inner membrane rhomboid peptidase PARL is known to participate in critical signalling cascades, its role in apoptosis has remained unclear. PARL is now shown to process the mitochondrial pro-apoptotic protein Smac (also known as DIABLO) for its subsequent release into the cytosol where it antagonizes XIAP-mediated caspase inhibition to promote apoptosis.
- Naotada Ishihara
- & Katsuyoshi Mihara
-
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
-
Article |
PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis
Saita et al. show that PARL cleaves Smac (also known as DIABLO) to generate an IAP-binding motif required for its apoptotic activity, identifying PARL-mediated Smac processing as a pro-apoptotic mitochondrial pathway.
- Shotaro Saita
- , Hendrik Nolte
- & Thomas Langer
-
News & Views |
Targeting mutant p53 through the mevalonate pathway
It is well established that mutant forms of the p53 tumour suppressor acquire pro-oncogenic activities. Inhibition of the mevalonate pathway is now shown to promote degradation of select oncogenic mutant p53 proteins, indicating that destabilization of mutant p53 could be a promising therapeutic strategy.
- William Freed-Pastor
- & Carol Prives
-
Article |
DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway
Iwakuma and colleagues report that statins, through their action on the mevalonate pathway, lead to the ubiquitin-mediated degradation of misfolded mutant p53 by impairing its interaction with the Hsp40 family member, DNAJA1.
- Alejandro Parrales
- , Atul Ranjan
- & Tomoo Iwakuma
-
News & Views |
p53 mutations promote proteasomal activity
p53 mutations occur very frequently in human cancer. Besides abrogating the tumour suppressive functions of wild-type p53, many of those mutations also acquire oncogenic gain-of-function activities. Augmentation of proteasome activity is now reported as a common gain-of-function mechanism shared by different p53 mutants, which promotes cancer resistance to proteasome inhibitors.
- Moshe Oren
- & Eran Kotler
Adding a transcription-coupled repair pathway