Stimulation of the innate immune system by foreign RNA elicits a potent interferon response and can trigger cell death. The mechanisms by which cells balance a robust response with cell-intrinsic lethality are still bein...Stimulation of the innate immune system by foreign RNA elicits a potent interferon response and can trigger cell death. The mechanisms by which cells balance a robust response with cell-intrinsic lethality are still being uncovered. Here, using genome-wide CRISPR-Cas9 genetic screens with triphosphorylated RNA stimulation, we discover that promyelocytic leukaemia (PML) nuclear body-localized speckled protein 110 (SP110) is a potent inhibitor of type 1 interferon-driven cell death. Death suppression by SP110 counteracts a toxic activity of SP100, a major constituent of PML bodies. Loss of SP110 leads to mitotic retention of SP100 and PML bodies, which associate with and perturb segregating chromosomes, leading to micronucleus formation, DNA damage and genotoxic cell death. A combination of cryo-electron microscopy, AlphaFold modelling and cellular biochemistry reveals that SP110 dissolves toxic SP100 oligomers via necessary and sufficient direct interactions between their caspase activation and recruitment domains. These data reveal the critical roles of SP100 and SP110 in governing the disassembly of PML bodies during mitosis, as well as the repercussions if this process is misregulated.
Liu M, Vandekeere A, Liu XZ
… +14 more, Schenck S, Fernández-García J, Tricot T, Peng-Winkler Y, Demicco M, Broekaert D, Vermeire I, Theile J, Zels G, Pabba A, Desmedt C, Brunner JD, Altea-Manzano P, Fendt SM
Nat Cell Biol
· 2026 Apr · PMID 41826695
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Acetylation is frequently dysregulated in cancer, and both acetyltransferase and deacetylase inhibitors are being evaluated at various stages of preclinical and clinical development. However, how the expression of acetyl...Acetylation is frequently dysregulated in cancer, and both acetyltransferase and deacetylase inhibitors are being evaluated at various stages of preclinical and clinical development. However, how the expression of acetyltransferases and deacetylases is regulated remains often elusive. We focused on the lysine acetyltransferase 2A (KAT2A) as it is important in multiple cancer indications with a clinical inhibitor in development. We discovered that KAT2A expression is regulated by palmitoylation in breast cancer-derived metastases. Specifically, we find that the palmitoyltransferase DHHC20 (gene name ZDHHC20) palmitoylates transmembrane 4L six family member 1 (TM4SF1) promoting its plasma membrane localization. This in turn fosters phosphorylation of the signal transducer and activator of transcription 3 (STAT3), which we identify as a transcriptional regulator of KAT2A. Accordingly, Zdhhc20 and Tm4sf1 silencing as well as expression of a Tm4sf1 double palmitoylation mutant decreases lung metastasis growth, which is rescued by Kat2a expression. We detect evidence of this palmitoylation-induced regulation of KAT2A in lung metastasis samples from patients with breast cancer. Thus, we show that palmitoylation can orchestrate the expression of a global acetylation regulator in lung metastases.
Zhang YY, Han Y, Tan YT
… +17 more, Lu YX, Ma MY, Zheng YQ, Chen HJ, Fu HY, Mo HY, Wu QN, Luo XJ, Liao K, Chen WQ, Zeng ZL, Piao HL, Du HL, Lin JZ, Tian T, Xu RH, Ju HQ
Nat Cell Biol
· 2026 Apr · PMID 41813885
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The peritumoural adipose tissue (PAT) is a key contributor to cancer therapy resistance, yet its role in regulating ferroptosis remains unclear. Here we demonstrate that PAT confers ferroptosis resistance to cancer cells...The peritumoural adipose tissue (PAT) is a key contributor to cancer therapy resistance, yet its role in regulating ferroptosis remains unclear. Here we demonstrate that PAT confers ferroptosis resistance to cancer cells by upregulating ferritin (FTH1/FTL) and sequestering intracellular iron. PAT-derived kynurenine (KYN) was identified as the principal mediator. KYN is taken up by cancer cells and metabolized to 3-hydroxykynurenine, which directly binds to nuclear receptor coactivator 4 (NCOA4). This interaction inhibits NCOA4-mediated ferritinophagy, preventing ferritin degradation and limiting the free iron pool required for ferroptosis. In murine models, pharmacological inhibition of the KYN pathway synergized with PD-1 blockade to overcome ferroptosis resistance and suppress tumour progression. These findings reveal a PAT-KYN-ferritinophagy axis that promotes ferroptosis resistance, highlighting the potential of targeting adipose-tumour cross-talk to enhance immunotherapy in PAT-associated tumours.
Whether pyroptosis is controllable and reversible remains an enigma. Here we revealed that autophagy could eliminate the pore-formed N terminus of GSDME (GSDME-NT) located on membranes at different locations, suppressing...Whether pyroptosis is controllable and reversible remains an enigma. Here we revealed that autophagy could eliminate the pore-formed N terminus of GSDME (GSDME-NT) located on membranes at different locations, suppressing pyroptosis. Crucially, GSDME-NT on the plasma membrane was eliminated through endocytic internalization, where GSDME-NT-laden vesicles were targeted and degraded as intact units. Specifically, GSDME-NT pores on the plasma membrane induced endocytosis, generating endocytosed but leaky vesicles carrying GSDME-NT. Leakage prevented acidification, necessitating further degradation through autophagy. Upon endocytosis, GSDME-NT on the vesicle membrane was labelled with ubiquitin by calcium-activated E3 ligase NEDD4L. These labelled vesicles were recognized by TOLLIP, guiding subsequent autophagosome formation, and enabling further acidification, fusion with lysosomes and eventual GSDME-NT degradation. Furthermore, in several tumour models, either disturbing autophagy or interfering with the recognition of GSDME-NT vesicles by targeting TOLLIP increased tumour cell pyroptosis, activating antitumour immunity and promoting chemotherapeutic efficacy.
Tao T, Feng X, Yang Y
… +23 more, Liu B, Liang J, Chen Z, Wang S, Zhao J, Yang X, Huo L, Zhang Y, Gan Z, Wu W, Zeng J, Huang Y, Ye Y, Xu X, Yu J, Hong R, Guan H, Wu J, Xia L, He W, Li B, Cai J, Li M
How cancer cells couple metabolic stress sensing to orchestrate specific survival programmes is a key question. Here we show a long non-coding RNA (lncRNA)-guided epitranscriptomic mechanism orchestrating metabolic adapt...How cancer cells couple metabolic stress sensing to orchestrate specific survival programmes is a key question. Here we show a long non-coding RNA (lncRNA)-guided epitranscriptomic mechanism orchestrating metabolic adaptation by controlling the stability of master stress regulator ATF4. Glucose or glutamine deprivation induces endoplasmic reticulum stress via reactive oxygen species-NRF2-dependent transcription of the lncRNA DAMER. Following its demethylation and nuclear retention by the mA-eraser ALKBH5, DAMER acts as a scaffold, guiding ALKBH5 to demethylate and stabilize ATF4 mRNA through specific base-pairing. This provides an alternative post-transcriptional pathway for ATF4 upregulation, rewiring asparagine metabolism to promote cancer cell survival under stress. Furthermore, we identified the US FDA-approved drug elbasvir as a potent inhibitor of the DAMER-ALKBH5 interaction. Elbasvir dismantles this adaptive programme, targeting tumour asparagine dependency and exhibiting potent antitumour effects in preclinical models. Our findings reveal a paradigm for lncRNA-guided RNA demethylation that solves a target specificity enigma and offers a strategy targeting metabolic adaptation in cancer.
Betrancourt A, Cinko MT, Varanda AB
… +16 more, Arias M, Uranga-Murillo I, Peña N, Kaps LM, Chau LF, Buratti B, Brägelmann J, de Miguel D, Becker K, Casper R, Martin R, Alcami A, Ferguson BJ, Pardo J, Rieser E, Walczak H
Nat Cell Biol
· 2026 Mar · PMID 41792265
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Pattern recognition receptor (PRR)-induced interferon (IFN) is critical for effective immunity. The PRRs Toll-like receptor (TLR) 3, TLR4 and cyclic GMP-AMP synthase (cGAS), together with the stimulator of IFN genes (STI...Pattern recognition receptor (PRR)-induced interferon (IFN) is critical for effective immunity. The PRRs Toll-like receptor (TLR) 3, TLR4 and cyclic GMP-AMP synthase (cGAS), together with the stimulator of IFN genes (STING), signal through TANK-binding kinase 1 (TBK1), which activates the type-I/III IFN-inducing transcription factor interferon-response factor 3 (IRF3). The mechanism by which these PRRs activate TBK1 remains unresolved. Here we show that lysine-11 (K11)-linked ubiquitination drives TBK1 activation by these PRRs. The E3 ligase ANKIB1 attaches K11-linked ubiquitin chains to components of the TLR3- and cGAS-STING-induced signalosomes. This facilitates Optineurin recruitment to these complexes, in turn enabling recruitment and activation of TBK1 and IRF3, defining an uncharacterized signalling axis. In mice, ANKIB1 deficiency dampens IFN induction via TLR3 and cGAS-STING, reducing interferonopathy and compromising protection against HSV-1, respectively. Together, our results demonstrate an unanticipated and critical role for ANKIB1-generated K11-linked ubiquitination in the immune response activated by cGAS-STING, TLR3 and TLR4.
Lee JH, Tingey M, Zhang Z
… +15 more, Buerger F, Hong J, Zhang G, Yang M, Du B, Jeong JH, John KA, Tamayo IM, Zhao QD, Hildebrandt F, Đurišić M, Stajić N, Spasojević B, Yang W, Xu K
Nat Cell Biol
· 2026 Mar · PMID 41786887
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Nuclear export of messenger RNAs (mRNAs) through nuclear pore complexes (NPCs) is a critical step in gene expression. Although N-adenosine methylation (mA) has been implicated in this process, the underlying mechanism re...Nuclear export of messenger RNAs (mRNAs) through nuclear pore complexes (NPCs) is a critical step in gene expression. Although N-adenosine methylation (mA) has been implicated in this process, the underlying mechanism remains obscure. Here we demonstrate, using single-molecule imaging, that mA markedly accelerates the nuclear export of messenger ribonucleoproteins (mRNPs) by increasing export efficiency and shortening export time through NPCs. We further show that the mA methyltransferase METTL3 localizes at NPCs and functionally associates with the nucleoporin NUP93 to promote the efficient export of mA-modified mRNPs. The disruption of this functional association between METTL3 and NUP93 substantially impairs overall mRNP export efficiency. Notably, a steroid-resistant nephrotic syndrome (SRNS)-associated NUP93 variant (c.1162C>T, p.Arg388Trp) fails to associate with METTL3, resulting in the defective nuclear export of key methylated mRNAs required for kidney function. Together, our findings define an mA-METTL3-NUP93 regulatory axis for nuclear mRNA export with broad implications for human disease.
The amnion is a transient extra-embryonic tissue whose formation, known as amniogenesis, is vital to amniote embryogenesis. The growing body of knowledge on amniotic lineage emergence and functions has enabled a more com...The amnion is a transient extra-embryonic tissue whose formation, known as amniogenesis, is vital to amniote embryogenesis. The growing body of knowledge on amniotic lineage emergence and functions has enabled a more comprehensive understanding of the underlying molecular mechanisms and thus may inspire future improvement in stem cell-based amniogenic models. In this Review we first introduce cavitation amniogenesis as a hallmark of human peri-implantation embryogenesis before addressing how cavitation amniogenesis is similar in humans and non-human primates but contrasts with folding amniogenesis in other amniotes such as mice and pigs. We also highlight the ongoing debate of whether primate amniogenesis harbours lineage plasticity for specifying germ cell fate and further discuss the two-wave amniogenesis model and its basis on the pluripotency transition. Finally, we summarize the potential of the recent stem cell-based human embryo models in elucidating amniotic formation and functions.
Nat Cell Biol
· 2026 Mar · PMID 41772090
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Coordination between growth and nuclear division is a common cell feature. In some syncytia, nuclei divide asynchronously throughout the cell but growth occurs only at discrete locations, raising the question how the pro...Coordination between growth and nuclear division is a common cell feature. In some syncytia, nuclei divide asynchronously throughout the cell but growth occurs only at discrete locations, raising the question how the processes are locally regulated and globally coordinated. In the syncytial fungus Ashbya gossypii, both cell cycle progression and hyphal elongation require condensates formed by the protein Whi3 in complex with distinct mRNA species. Here we show that Whi3 condensates are enriched for translation regulators and are associated with local, spatially patterned translation of specific target RNAs near nuclei and growth sites. Whi3-RNA condensates can both promote and repress mRNA translation in an RNA- and condensate size-dependent manner in vitro. Condensate interfaces are sites of translation, tunable by condensate composition, RNA valency and protein charge state in vitro. Together, these data suggest that Whi3 condensates can generate a continuum of translation states that vary depending on the subcellular location and resident RNA sequences.
Xia K, Zhang S, Peng H
… +24 more, Chen H, Yang C, Yu J, Luo P, Lu Q, Chen H, Huang L, Xiong Y, Zhao L, Jia L, Li L, Qiu Y, Guo Y, Liu C, Fan H, Dai Z, Liu G, Ke Q, Wang T, Li W, Chen L, Deng C, Xiao H, Xiang AP
Nat Cell Biol
· 2026 Apr · PMID 41760931
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Testosterone production by testicular Leydig cells (LCs) in male mammals is energetically demanding and prone to mitochondrial damage. Despite these challenges, LCs exhibit remarkable longevity and minimal turnover, sugg...Testosterone production by testicular Leydig cells (LCs) in male mammals is energetically demanding and prone to mitochondrial damage. Despite these challenges, LCs exhibit remarkable longevity and minimal turnover, suggesting the existence of specialized mechanisms that maintain LC mitochondrial homeostasis under such constrains. Here we identify a mitochondrial transfer network between LCs and different testicular macrophage (tMac) subpopulations. Leydig cells release extracellular vesicles containing defective mitochondria, which are eliminated by CD206 tMacs in a TREM2-dependent process. Deletion of Trem2 in tMacs disrupts this transfer, leading to impaired testosterone synthesis. Conversely, LCs acquire extracellular vesicles containing functional mitochondria from MHCII tMacs through ITGβ1-VCAM1 interactions. Loss of Vcam1 in LCs hinders this mitochondrial transfer, thereby compromising testosterone production. Together, our findings reveal an unrecognized mitochondrial transfer network between LCs and tMacs that safeguards LC homeostasis and testosterone production, offering valuable insights into intercellular communication mechanisms that maintain tissue homeostasis.
Heinen S, Tiku V, Grevel A
… +21 more, Hugenroth M, Ellenrieder L, Steymans I, Licheva M, Bonini S, Oeljeklaus S, Okon N, Lambertz J, Poppe S, Song J, Fester L, Meisinger C, Warscheid B, Eckhardt M, Wiedemann N, Winter D, Kraft C, den Brave F, Bohnert M, Pfanner N, Becker T
Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular comp...Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular compartments. The mitochondrial import (MIM) complex functions as main translocase for importing the precursors of more than 90% of integral outer-membrane proteins. Here we report that the MIM complex performs a second major function in lipid-droplet homeostasis. Lipid droplets are crucial in cellular lipid metabolism and as storage organelles for neutral lipids. The lipid metabolism enzyme Ayr1 captures the MIM complex, promoting the formation of mitochondria-lipid droplet contact sites. MIM and Ayr1 enhance the lipid droplet number in cells. Ayr1 binds to MIM via its single hydrophobic segment in a substrate-mimicry mechanism but remains bound and is not released into the outer membrane. The functional diversity is mediated by different MIM complexes: MIM-Ayr1 for recruiting lipid droplets and MIM-preprotein for protein insertion into the outer membrane. Our work uncovers translocase capture as a mechanism for functional conversion of a membrane protein complex from protein insertion to lipid metabolism.
Intranuclear inclusions are defining features of many neurodegenerative diseases, yet their assembly mechanisms and pathological roles remain poorly understood. Here, we investigate polyglycine (polyG) inclusions in neur...Intranuclear inclusions are defining features of many neurodegenerative diseases, yet their assembly mechanisms and pathological roles remain poorly understood. Here, we investigate polyglycine (polyG) inclusions in neuronal intranuclear inclusion disease (NIID) and show that they recruit intrinsically disordered proteins to form stratified, immobile condensates that disrupt nuclear protein quality control and DNA damage repair. Leveraging their ordered and stepwise assembly, we identify promyelocytic leukaemia protein (PML) as a key factor that actively recognizes and eliminates polyG inclusions through chaperone-mediated disaggregation and proteasome-dependent degradation. Engineered PML variants selectively clear both nuclear and cytoplasmic aggregates, including polyG, polyGA, polyQ, TDP-43 and SOD1. Systemic PML delivery alleviates cognitive and motor deficits in mouse models of NIID and TDP-43 proteinopathy. These findings uncover a conserved spatial organization of nuclear inclusions and establish PML as a therapeutic effector for neurodegenerative diseases linked to protein aggregation.
Lewis R, Sinigiani V, Maziak N
… +10 more, Koos K, Bersaglieri C, Zemp I, Ashiono C, Ciaudo C, Horvath P, Vaquerizas JM, Santoro R, Sharma P, Kutay U
Nat Cell Biol
· 2026 Mar · PMID 41735607
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In most eukaryotic cells, euchromatin is localized in the nuclear interior, whereas heterochromatin is enriched at the nuclear envelope (NE). This conventional chromatin organization is established by heterochromatin tet...In most eukaryotic cells, euchromatin is localized in the nuclear interior, whereas heterochromatin is enriched at the nuclear envelope (NE). This conventional chromatin organization is established by heterochromatin tethering to the NE; however, its importance for cellular homeostasis is largely unexplored. One tether is constituted by the lamin B receptor (LBR) in mammals, but the enigmatic nature of other redundant tethers has hampered functional analyses. Here we demonstrate that downregulation of abundant, ubiquitous NE proteins can induce the global detachment of heterochromatin from the NE and its repositioning to the nuclear interior. We identify LBR and lamina-associated polypeptide 2 (LAP2) as key factors for peripheral heterochromatin positioning in differentiated and pluripotent mammalian cells. Their long-term loss leads to changes in three-dimensional chromatin organization and a reduction in repressive epigenetic marks, especially H3K27me3. These changes are associated with massive deregulation of gene expression, activation of antiviral innate immunity, and defects in cell fate determination.