Andreas Kohler, Andreas Carlström, Hendrik Nolte, Verena Kohler, Sung-Jun Jung, Sagar Sridhara, Takashi Tatsuta, Jens Berndtsson, Thomas Langer, Martin Ott
Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent polypeptides at ribosomes or, if this fails, ensure their degradation. Although well studied for cytosolic protein biogenesis, it is not understood how these processes work for mitochondrially encoded proteins, key subunits of the oxidative phosphorylation (OXPHOS) system. Here, we identify dedicated hubs in proximity to mitoribosomal tunnel exits coordinating mitochondrial protein biogenesis and quality control...
September 21, 2023: Molecular Cell
Lixin He, Jinxin Chen, Pinwei Deng, Shumei Huang, Pian Liu, Chanjuan Wang, Xinjian Huang, Yue Li, Boyu Chen, Dongni Shi, Yunyun Xiao, Xiangfu Chen, Ying Ouyang, Libing Song, Chuyong Lin
Cyst(e)ine is a key precursor for the synthesis of glutathione (GSH), which protects cancer cells from oxidative stress. Cyst(e)ine is stored in lysosomes, but its role in redox regulation is unclear. Here, we show that breast cancer cells upregulate major facilitator superfamily domain containing 12 (MFSD12) to increase lysosomal cyst(e)ine storage, which is released by cystinosin (CTNS) to maintain GSH levels and buffer oxidative stress. We find that mTORC1 regulates MFSD12 by directly phosphorylating residue T254, while mTORC1 inhibition enhances lysosome acidification that activates CTNS...
September 20, 2023: Molecular Cell
Yohei Abe, Eric R Kofman, Maria Almeida, Zhengyu Ouyang, Filipa Ponte, Jasmine R Mueller, Grisel Cruz-Becerra, Mashito Sakai, Thomas A Prohaska, Nathanael J Spann, Ana Resende-Coelho, Jason S Seidman, Joshua D Stender, Havilah Taylor, Weiwei Fan, Verena M Link, Isidoro Cobo, Johannes C M Schlachetzki, Takao Hamakubo, Kristen Jepsen, Juro Sakai, Michael Downes, Ronald M Evans, Gene W Yeo, James T Kadonaga, Stavros C Manolagas, Michael G Rosenfeld, Christopher K Glass
The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression...
September 14, 2023: Molecular Cell
Lizhen Chen, Zhao Zhang, Qinyu Han, Barun K Maity, Leticia Rodrigues, Emily Zboril, Rashmi Adhikari, Su-Hyuk Ko, Xin Li, Shawn R Yoshida, Pengya Xue, Emilie Smith, Kexin Xu, Qianben Wang, Tim Hui-Ming Huang, Shasha Chong, Zhijie Liu
Transcription factors (TFs) activate enhancers to drive cell-specific gene programs in response to signals, but our understanding of enhancer assembly during signaling events is incomplete. Here, we show that androgen receptor (AR) forms condensates through multivalent interactions mediated by its N-terminal intrinsically disordered region (IDR) to orchestrate enhancer assembly in response to androgen signaling. AR IDR can be substituted by IDRs from selective proteins for AR condensation capacity and its function on enhancers...
September 14, 2023: Molecular Cell
Kamila Delaney, Nicole Weiss, Geneviève Almouzni
Histone variants provide versatility in the basic unit of chromatin, helping to define dynamic landscapes and cell fates. Maintaining genome integrity is paramount for the cell, and it is intimately linked with chromatin dynamics, assembly, and disassembly during DNA transactions such as replication, repair, recombination, and transcription. In this review, we focus on the family of H3 variants and their dynamics in space and time during the cell cycle. We review the distinct H3 variants' specific features along with their escort partners, the histone chaperones, compiled across different species to discuss their distinct importance considering evolution...
September 14, 2023: Molecular Cell
Rahul Bhowmick, Ian D Hickson, Ying Liu
Mitotic DNA synthesis (MiDAS) is an unusual form of DNA replication that occurs during mitosis. Initially, MiDAS was characterized as a process associated with intrinsically unstable loci known as common fragile sites that occurs after cells experience DNA replication stress (RS). However, it is now believed to be a more widespread "salvage" mechanism that is called upon to complete the duplication of any under-replicated genomic region. Emerging data suggest that MiDAS is a DNA repair process potentially involving two or more pathways working in parallel or sequentially...
September 8, 2023: Molecular Cell
Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou
Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion...
September 7, 2023: Molecular Cell
Jurgita Paukštytė, Rosa María López Cabezas, Yuehan Feng, Kai Tong, Daniela Schnyder, Ellinoora Elomaa, Pavlina Gregorova, Matteo Doudin, Meeri Särkkä, Jesse Sarameri, Alice Lippi, Helena Vihinen, Juhana Juutila, Anni Nieminen, Petri Törönen, Liisa Holm, Eija Jokitalo, Anita Krisko, Juha Huiskonen, L Peter Sarin, Ville Hietakangas, Paola Picotti, Yves Barral, Juha Saarikangas
Aging is associated with progressive phenotypic changes. Virtually all cellular phenotypes are produced by proteins, and their structural alterations can lead to age-related diseases. However, we still lack comprehensive knowledge of proteins undergoing structural-functional changes during cellular aging and their contributions to age-related phenotypes. Here, we conducted proteome-wide analysis of early age-related protein structural changes in budding yeast using limited proteolysis-mass spectrometry (LiP-MS)...
September 6, 2023: Molecular Cell
Noa Liberman, M Hafiz Rothi, Maxim V Gerashchenko, Christiane Zorbas, Konstantinos Boulias, Fiona G MacWhinnie, Albert Kejun Ying, Anya Flood Taylor, Joseph Al Haddad, Hiroki Shibuya, Lara Roach, Anna Dong, Scarlett Dellacona, Denis L J Lafontaine, Vadim N Gladyshev, Eric Lieberman Greer
Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labeling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans (C. elegans). We find heritable methylation in DNA, RNA, proteins, and lipids. We find that parental starvation elicits reduced fertility, increased heat stress resistance, and extended longevity in fed, naïve progeny...
September 6, 2023: Molecular Cell
Nathan Jentink, Carson Purnell, Brianna Kable, Matthew T Swulius, Sergei A Grigoryev
Nucleosome chains fold and self-associate to form higher-order structures whose internal organization is unknown. Here, cryoelectron tomography (cryo-ET) of native human chromatin reveals intrinsic folding motifs such as (1) non-uniform nucleosome stacking, (2) intermittent parallel and perpendicular orientations of adjacent nucleosome planes, and (3) a regressive nucleosome chain path, which deviates from the direct zigzag topology seen in reconstituted nucleosomal arrays. By examining the self-associated structures, we observed prominent nucleosome stacking in cis and anti-parallel nucleosome interactions, which are consistent with partial nucleosome interdigitation in trans...
August 31, 2023: Molecular Cell
Shaoni Mukhopadhyay, Maria E Amodeo, Amy S Y Lee
Cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating gene programs necessary for survival. Here, we show that the integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d that acts as a critical effector to control core stress response orchestrators, the translation factor eIF2α and the transcription factor ATF4. We find that during persistent stress, eIF3d activates the translation of the kinase GCN2, inducing eIF2α phosphorylation and inhibiting general protein synthesis...
August 30, 2023: Molecular Cell
Zhong Han, George A Moore, Richard Mitter, David Lopez Martinez, Li Wan, A Barbara Dirac Svejstrup, David S Rueda, Jesper Q Svejstrup
RNA polymerase II (RNAPII) transcription involves initiation from a promoter, transcriptional elongation through the gene, and termination in the terminator region. In bacteria, terminators often contain specific DNA elements provoking polymerase dissociation, but RNAPII transcription termination is thought to be driven entirely by protein co-factors. We used biochemical reconstitution, single-molecule studies, and genome-wide analysis in yeast to study RNAPII termination. Transcription into natural terminators by pure RNAPII results in spontaneous termination at specific sequences containing T-tracts...
August 30, 2023: Molecular Cell
Kiyofumi Hamashima, Ka Wai Wong, Tsz Wing Sam, Jia Hao Jackie Teo, Reshma Taneja, Minh T N Le, Qi-Jing Li, Jacob H Hanna, Hu Li, Yuin-Han Loh
N6 -methyladenosine (m6 A) RNA modification plays important roles in the governance of gene expression and is temporally regulated in different cell states. In contrast to global m6 A profiling in bulk sequencing, single-cell technologies for analyzing m6 A heterogeneity are not extensively established. Here, we developed single-nucleus m6A-CUT&Tag (sn-m6A-CT) for simultaneous profiling of m6 A methylomes and transcriptomes within a single nucleus using mouse embryonic stem cells (mESCs). m6A-CT is capable of enriching m6 A-marked RNA molecules in situ, without isolating RNAs from cells...
August 25, 2023: Molecular Cell
Robert V Swanda, Quanquan Ji, Xincheng Wu, Jingyue Yan, Leiming Dong, Yuanhui Mao, Saori Uematsu, Yizhou Dong, Shu-Bing Qian
The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway...
August 24, 2023: Molecular Cell
Korrie L Mack, Hanna Kim, Edward M Barbieri, JiaBei Lin, Sylvanne Braganza, Meredith E Jackrel, Jamie E DeNizio, Xiaohui Yan, Edward Chuang, Amber Tariq, Ryan R Cupo, Laura M Castellano, Kim A Caldwell, Guy A Caldwell, James Shorter
Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity...
August 22, 2023: Molecular Cell
Karen Betancourt Moreira, Miranda P Collier, Alexander Leitner, Kathy H Li, Ivana L Serrano Lachapel, Frank McCarthy, Kwadwo A Opoku-Nsiah, Fabián Morales-Polanco, Natália Barbosa, Daniel Gestaut, Rahul S Samant, Soung-Hun Roh, Judith Frydman
How the essential eukaryotic chaperonin TRiC/CCT assembles from eight distinct subunits into a unique double-ring architecture remains undefined. We show TRiC assembly involves a hierarchical pathway that segregates subunits with distinct functional properties until holocomplex (HC) completion. A stable, likely early intermediate arises from small oligomers containing CCT2, CCT4, CCT5, and CCT7, contiguous subunits that constitute the negatively charged hemisphere of the TRiC chamber, which has weak affinity for unfolded actin...
August 18, 2023: Molecular Cell
Inés Paniagua, Jacqueline J L Jacobs
Translesion synthesis (TLS) DNA polymerases were originally described as error-prone enzymes involved in the bypass of DNA lesions. However, extensive research over the past few decades has revealed that these enzymes play pivotal roles not only in lesion bypass, but also in a myriad of other cellular processes. Such processes include DNA replication, DNA repair, epigenetics, immune signaling, and even viral infection. This review discusses the wide range of functions exhibited by TLS polymerases, including their underlying biochemical mechanisms and associated mutagenicity...
August 18, 2023: Molecular Cell
Zhiheng Deng, Huasong Ai, Maoshen Sun, Zebin Tong, Yunxiang Du, Qian Qu, Liying Zhang, Ziyu Xu, Shixian Tao, Qiang Shi, Jia-Bin Li, Man Pan, Lei Liu
Histone H2B monoubiquitylation plays essential roles in chromatin-based transcriptional processes. A RING-type E3 ligase (yeast Bre1 or human RNF20/RNF40) and an E2 ubiquitin-conjugating enzyme (yeast Rad6 or human hRAD6A), together, precisely deposit ubiquitin on H2B K123 in yeast or K120 in humans. Here, we developed a chemical trapping strategy and successfully captured the transient structures of Bre1- or RNF20/RNF40-mediated ubiquitin transfer from Rad6 or hRAD6A to nucleosomal H2B. Our structures show that Bre1 and RNF40 directly bind nucleosomal DNA, exhibiting a conserved E3/E2/nucleosome interaction pattern from yeast to humans for H2B monoubiquitylation...
August 17, 2023: Molecular Cell
Gayoung Seo, Clinton Yu, Han Han, Li Xing, Rebecca Elizabeth Kattan, Jeongmin An, Amrutha Kizhedathu, Bing Yang, Annabella Luo, Abigail L Buckle, Delia Tifrea, Robert Edwards, Lan Huang, Huai-Qiang Ju, Wenqi Wang
The Hippo pathway is known for its crucial involvement in development, regeneration, organ size control, and cancer. While energy stress is known to activate the Hippo pathway and inhibit its effector YAP, the precise role of the Hippo pathway in energy stress response remains unclear. Here, we report a YAP-independent function of the Hippo pathway in facilitating autophagy and cell survival in response to energy stress, a process mediated by its upstream components MAP4K2 and STRIPAK. Mechanistically, energy stress disrupts the MAP4K2-STRIPAK association, leading to the activation of MAP4K2...
August 17, 2023: Molecular Cell
Alexander J McQuown, Anjali R Nelliat, Dvir Reif, Ibrahim M Sabbarini, Britnie Santiago Membreno, Colin Chih-Chien Wu, Vladimir Denic
General protein folding is mediated by chaperones that utilize ATP hydrolysis to regulate client binding and release. Zinc-finger protein 1 (Zpr1) is an essential ATP-independent chaperone dedicated to the biogenesis of eukaryotic translation elongation factor 1A (eEF1A), a highly abundant GTP-binding protein. How Zpr1-mediated folding is regulated to ensure rapid Zpr1 recycling remains an unanswered question. Here, we use yeast genetics and microscopy analysis, biochemical reconstitution, and structural modeling to reveal that folding of eEF1A by Zpr1 requires GTP hydrolysis...
August 16, 2023: Molecular Cell
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