Cell Reports
All content is freely available to readers and supported through open access

May 10, 2022

Volume 39Issue 6
Open Access
An image of the apical tip of a Drosophila testis, with somatic cell membranes in cyan and mitochondria in yellow. Sainz de la Maza et al. show that in the Drosophila testis, somatic stem cell differentiation is coordinated with cell cycle exit by the transcription factor E2f1/Dp, which inhibits mitochondrial activity in cycling cells. Inhibition of E2f1/Dp by the Retinoblastoma homologue Rbf allows increased mitochondrial activity and permits differentiation. Image by Diego Sainz de la Maza....
An image of the apical tip of a Drosophila testis, with somatic cell membranes in cyan and mitochondria in yellow. Sainz de la Maza et al. show that in the Drosophila testis, somatic stem cell differentiation is coordinated with cell cycle exit by the transcription factor E2f1/Dp, which inhibits mitochondrial activity in cycling cells. Inhibition of E2f1/Dp by the Retinoblastoma homologue Rbf allows increased mitochondrial activity and permits differentiation. Image by Diego Sainz de la Maza.


  • Nasally delivered interferon-λ protects mice against infection by SARS-CoV-2 variants including Omicron

    • Zhenlu Chong,
    • Courtney E. Karl,
    • Peter J. Halfmann,
    • Yoshihiro Kawaoka,
    • Emma S. Winkler,
    • Shamus P. Keeler,
    • Michael J. Holtzman,
    • Jinsheng Yu,
    • Michael S. Diamond
    Chong et al. show that intranasally delivered murine IFN-λ2 protects mice against historical, B.1.351 (Beta), and B.1.1.529 (Omicron) SARS-CoV-2 infection in the upper and lower respiratory tracts without excessive inflammation. In the lung, IFN-λ is produced mainly by epithelial cells and acts on stromal cells to protect against of SARS-CoV-2 infection.
  • Interactomic analysis reveals a homeostatic role for the HIV restriction factor TRIM5α in mitophagy

    • Bhaskar Saha,
    • Michelle Salemi,
    • Geneva L. Williams,
    • Seeun Oh,
    • Michael L. Paffett,
    • Brett Phinney,
    • Michael A. Mandell
    The protein TRIM5α is well known for its roles in antiretroviral defense. Saha et al. show that TRIM5α also has key homeostatic functions. They report that TRIM5α helps to maintain mitochondrial quality control by enabling the autophagy-dependent removal of damaged mitochondria (mitophagy).
  • KSHV episome tethering sites on host chromosomes and regulation of latency-lytic switch by CHD4

    • Ashish Kumar,
    • Yuanzhi Lyu,
    • Yuichi Yanagihashi,
    • Chanikarn Chantarasrivong,
    • Vladimir Majerciak,
    • Michelle Salemi,
    • Kang-Hsin Wang,
    • Tomoki Inagaki,
    • Frank Chuang,
    • Ryan R. Davis,
    • Clifford G. Tepper,
    • Kazushi Nakano,
    • Chie Izumiya,
    • Michiko Shimoda,
    • Ken-ichi Nakajima,
    • Alexander Merleev,
    • Zhi-Ming Zheng,
    • Mel Campbell,
    • Yoshihiro Izumiya
    Kumar et al. perform Capture Hi-C to identify KSHV tethering sites on host chromosomes. They highlight that LANA interacts with CHD4, and KSHV episomes localize at CHD4 enriched regions. KSHV non-coding RNA binds and sequesters CHD4 during reactivation. This study furthers our understanding of the mechanism of the latency-lytic switch.
  • A TRUSTED targeted mass spectrometry assay for pan-herpesvirus protein detection

    • Michelle A. Kennedy,
    • Matthew D. Tyl,
    • Cora N. Betsinger,
    • Joel D. Federspiel,
    • Xinlei Sheng,
    • Jesse H. Arbuckle,
    • Thomas M. Kristie,
    • Ileana M. Cristea
    Herpesviruses encode many proteins, making it difficult to comprehensively monitor viral protein levels by traditional approaches. Kennedy et al. develop a set of targeted mass spectrometry-based assays for measuring herpesvirus protein levels spanning all virus subfamilies (α, β, and γ) and demonstrate their usefulness for a wide range of applications.
  • Adipose mitochondrial metabolism controls body growth by modulating systemic cytokine and insulin signaling

    • Shrivani Sriskanthadevan-Pirahas,
    • Michael J. Turingan,
    • Joel S. Chahal,
    • Erin Thorson,
    • Shahoon Khan,
    • Abdul Qadeer Tinwala,
    • Savraj S. Grewal
    Using Drosophila larvae, Sriskanthadevan-Pirahas et al. show how nutrient-dependent control of adipose mitochondrial metabolism controls body growth and development. Lowered mitochondrial bioenergetic activity specifically in the fat body is sufficient to accelerate development through altered adipokine control of systemic insulin signaling.
  • Lipogenesis mediated by OGR1 regulates metabolic adaptation to acid stress in cancer cells via autophagy

    • Smitha Pillai,
    • Iqbal Mahmud,
    • Rohit Mahar,
    • Crystal Griffith,
    • Michael Langsen,
    • Jonathan Nguyen,
    • Jonathan W. Wojtkowiak,
    • Pawel Swietach,
    • Robert A. Gatenby,
    • Marilyn M. Bui,
    • Matthew E. Merritt,
    • Patricia McDonald,
    • Timothy J. Garrett,
    • Robert J. Gillies
    Acid sensing is essential for cell survival under acidic growth conditions. Pillai et al. report that in response to extracellular acidosis, cells accumulate lipid droplets that are derived from autophagic breakdown of amino acids. This adaptive mechanism is triggered by the acid-sensing receptor OGR1 in breast cancer cells.
  • The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62

    • Juan F. Linares,
    • Tania Cid-Diaz,
    • Angeles Duran,
    • Marta Osrodek,
    • Anxo Martinez-Ordoñez,
    • Miguel Reina-Campos,
    • Hui-Hsuan Kuo,
    • Olivier Elemento,
    • M. Laura Martin,
    • Thekla Cordes,
    • Timothy C. Thompson,
    • Christian M. Metallo,
    • Jorge Moscat,
    • Maria T. Diaz-Meco
    Linares et al. describe a molecular mechanism for cancer-associated fibroblast activation. Tumor-secreted lactate downregulates p62 in the stroma by reducing NAD+, which impairs PARP-1 activity, blocking AP-1-mediated p62 transcription. PARP-1 inhibitors mimic lactate to induce stroma activation, suggesting that anti-stromal therapies might enhance their efficacy.
  • SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing promotes resistance of pancreatic cancer to gemcitabine

    • Zu-Wei Wang,
    • Jing-Jing Pan,
    • Jian-Fei Hu,
    • Jia-Qiang Zhang,
    • Long Huang,
    • Yi Huang,
    • Cheng-Yu Liao,
    • Can Yang,
    • Zhi-Wen Chen,
    • Yao-Dong Wang,
    • Bai-Yong Shen,
    • Yi-Feng Tian,
    • Shi Chen
    Abnormal splicing leads to gemcitabine chemoresistance in pancreatic cancer. Wang et al. show that SRSF3 promotes gemcitabine resistance of pancreatic cancer by regulating the splicing of lncRNA ANRIL, and that m6A methylation on ANRIL is essential for splicing. Targeting SRSF3 suppresses the splicing of ANRIL, suggesting a potential therapeutic strategy.
  • MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis

    • Yasutaka Hayashi,
    • Kimihito C. Kawabata,
    • Yosuke Tanaka,
    • Yasufumi Uehara,
    • Yo Mabuchi,
    • Koichi Murakami,
    • Akira Nishiyama,
    • Shigeru Kiryu,
    • Yusuke Yoshioka,
    • Yasunori Ota,
    • Tatsuki Sugiyama,
    • Keiko Mikami,
    • Moe Tamura,
    • Tsuyoshi Fukushima,
    • Shuhei Asada,
    • Reina Takeda,
    • Yuya Kunisaki,
    • Tomofusa Fukuyama,
    • Kazuaki Yokoyama,
    • Tomoyuki Uchida,
    • Masao Hagihara,
    • Nobuhiro Ohno,
    • Kensuke Usuki,
    • Arinobu Tojo,
    • Yoshio Katayama,
    • Susumu Goyama,
    • Fumio Arai,
    • Tomohiko Tamura,
    • Takashi Nagasawa,
    • Takahiro Ochiya,
    • Daichi Inoue,
    • Toshio Kitamura
    Hayashi et al. show that MDS cells impair osteolineage differentiation of MSCs via MDS-derived EVs, leading to bone marrow failure due to less supportive niche function. Indeed, enforced differentiation of MSCs or EV inhibition rescues the normal hematopoiesis. These findings highlight cancer-derived EVs and MSC axis in MDS pathogenesis.
  • PTBP1 promotes hematopoietic stem cell maintenance and red blood cell development by ensuring sufficient availability of ribosomal constituents

    • Matilda Rehn,
    • Anne Wenzel,
    • Anne-Katrine Frank,
    • Mikkel Bruhn Schuster,
    • Sachin Pundhir,
    • Nanna Jørgensen,
    • Kristoffer Vitting-Seerup,
    • Ying Ge,
    • Johan Jendholm,
    • Magali Michaut,
    • Erwin M. Schoof,
    • Tanja Lyholm Jensen,
    • Nicolas Rapin,
    • Russell T. Sapio,
    • Kasper Langebjerg Andersen,
    • Anders H. Lund,
    • Michele Solimena,
    • Martin Holzenberger,
    • Dimitri G. Pestov,
    • Bo Torben Porse
    Congenital ribosomopathies are caused by mutations in genes affecting ribosome biogenesis or function. Rehn et al. find that loss of the splicing regulator, PTBP1, within murine hematopoiesis is associated with reduced protein synthesis, anemia, and reduced stem cell function, thereby mirroring ribosomopathy. These findings identify PTBP1 as a ribosome-integrating factor.
  • Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction

    • Fatemeh Safi,
    • Parashar Dhapola,
    • Sarah Warsi,
    • Mikael Sommarin,
    • Eva Erlandsson,
    • Jonas Ungerbäck,
    • Rebecca Warfvinge,
    • Ewa Sitnicka,
    • David Bryder,
    • Charlotta Böiers,
    • Ram Krishna Thakur,
    • Göran Karlsson
    Safi et al. reveal a unique hematopoietic transition state, displaying concurrent stem- and multi-lineage chromatin-accessibility signatures captured by LSKFlt3intCD9high immunophenotype. LSKFlt3intCD9high cells represent extensively primed progenitors lacking self-renewal but bridging multipotency and lineage restriction. These findings permit analysis of how self-renewal and multipotency are lost in favor of lineage commitment.
  • Aryl hydrocarbon receptor signals in epithelial cells govern the recruitment and location of Helios+ Tregs in the gut

    • Yusuke Yoshimatsu,
    • Tomohisa Sujino,
    • Kentaro Miyamoto,
    • Yosuke Harada,
    • Shun Tanemoto,
    • Keiko Ono,
    • Satoko Umeda,
    • Kosuke Yoshida,
    • Toshiaki Teratani,
    • Takahiro Suzuki,
    • Yohei Mikami,
    • Nobuhiro Nakamoto,
    • Nobuo Sasaki,
    • Kaoru Takabayashi,
    • Naoki Hosoe,
    • Haruhiko Ogata,
    • Kazuaki Sawada,
    • Takeshi Imamura,
    • Akihiko Yoshimura,
    • Takanori Kanai
    Yoshimatsu et al. show that aryl hydrocarbon receptor (AhR) signaling in ECs governs the induction and localization of indigo naturalis (IN)-induced Helios+ Tregs in the colon both in the murine model and in ulcerative colitis patients.
  • Superinfection exclusion factors drive a history-dependent switch from vertical to horizontal phage transmission

    • Ines Staes,
    • Leonard E. Bäcker,
    • Kenneth Simoens,
    • Kjerstin De Winter,
    • Gasper Marolt,
    • William Cenens,
    • Sanne Wolput,
    • Alan R. Vazquez,
    • Peter Goos,
    • Rob Lavigne,
    • Kristel Bernaerts,
    • Abram Aertsen
    While a high phage-to-host ratio is typically expected to drive temperate phages towards lysogenic conversion of their host cells, Staes el al. reveal that P22 can make use of carrier-state dynamics and expression of its superinfection exclusion factors to raise a subpopulation of host cells for lytic consumption.
  • Identification of distinct non-myogenic skeletal-muscle-resident mesenchymal cell populations

    • Abigail P. Leinroth,
    • Anthony J. Mirando,
    • Douglas Rouse,
    • Yoshihiko Kobayahsi,
    • Purushothama Rao Tata,
    • Helen E. Rueckert,
    • Yihan Liao,
    • Jason T. Long,
    • Joe V. Chakkalakal,
    • Matthew J. Hilton
    Leinroth et al. explore the heterogeneity of Pdgfra+ muscle-resident mesenchymal cells, demonstrating that Pdgfra+ subpopulations have unique gene expression profiles, exhibit two distinct cell trajectories from a common progenitor, differ in their abilities to respond to muscle injuries, and show variable adipogenic and mineralizing capacities.
  • Single-cell transcriptomics provides insights into hypertrophic cardiomyopathy

    • Martijn Wehrens,
    • Anne E. de Leeuw,
    • Maya Wright-Clark,
    • Joep E.C. Eding,
    • Cornelis J. Boogerd,
    • Bas Molenaar,
    • Petra H. van der Kraak,
    • Diederik W.D. Kuster,
    • Jolanda van der Velden,
    • Michelle Michels,
    • Aryan Vink,
    • Eva van Rooij
    Wehrens et al. perform single-cell RNA sequencing on hearts from patients who suffer from hypertrophic cardiomyopathy (HCM). This reveals cardiomyocyte subpopulations, gene regulatory networks, transcription factors, and hypertrophy-related genes that might be relevant for pathogenesis of the disease.
  • Cell-cycle exit and stem cell differentiation are coupled through regulation of mitochondrial activity in the Drosophila testis

    • Diego Sainz de la Maza,
    • Silvana Hof-Michel,
    • Lee Phillimore,
    • Christian Bökel,
    • Marc Amoyel
    Stem cell differentiation is linked to their exit from the cell cycle. Here, Sainz de la Maza et al. identify the E2f/Dp transcription factor as an essential link between cell-cycle progression and stem cell identity. They show that E2f/Dp downregulates mitochondrial activity to inhibit differentiation in cycling cells.
  • Mitochondrial LETM1 drives ionic and molecular clock rhythms in circadian pacemaker neurons

    • Eri Morioka,
    • Yusuke Kasuga,
    • Yuzuki Kanda,
    • Saki Moritama,
    • Hayato Koizumi,
    • Tomoko Yoshikawa,
    • Nobuhiko Miura,
    • Masaaki Ikeda,
    • Haruhiro Higashida,
    • Todd C. Holmes,
    • Masayuki Ikeda
    Morioka et al. show critical functions of the mitochondrial cation antiporter LETM1 in cytosolic H+ and Ca2+ rhythms in Drosophila and rat circadian pacemaker neurons. LETM1 knockdown disturbs clock gene oscillations in both species, clarifying the mitochondrial coordination of clock function in pacemaker neurons.
  • Movement-specific signaling is differentially distributed across motor cortex layer 5 projection neuron classes

    • Stephen P. Currie,
    • Julian J. Ammer,
    • Brian Premchand,
    • Joshua Dacre,
    • Yufei Wu,
    • Constantinos Eleftheriou,
    • Matt Colligan,
    • Thomas Clarke,
    • Leah Mitchell,
    • A. Aldo Faisal,
    • Matthias H. Hennig,
    • Ian Duguid
    Currie et al. show that movement-type-specific information is routed through relatively small, distributed subpopulations of motor cortical layer 5B projection neurons. Using 2-photon population calcium imaging, they demonstrate that movement-invariant signaling dominates layer 5B population dynamics, whereas movement-specific signaling is differentially distributed across projection neuron classes.
  • A cerebellar origin of feedforward inhibition to the motor cortex in non-human primates

    • Abdulraheem Nashef,
    • Oren Cohen,
    • Steve I. Perlmutter,
    • Yifat Prut
    Nashef et al. use pharmacological manipulation to identify parvalbumin (PV) and pyramidal cells driven directly by cerebellar-thalamocortical input. Movement-related activity of PV cells starts earlier but is correlated with the activity of simultaneously recorded pyramidal cells. Feedforward inhibition may thus amplify cerebellar signals and suppress competing inputs.
  • Serotonin receptors contribute to dopamine depression of lateral inhibition in the nucleus accumbens

    • Dennis A. Burke,
    • Veronica A. Alvarez
    Burke and Alvarez find that, in the nucleus accumbens, dopamine depresses or potentiates lateral inhibition between projection neurons, depending on the specific synapses isolated. Dopamine depression of D2-MSN GABA transmission involves activation of 5-HT1B receptors, suggesting that cross-talk between monoamines and receptors plays a role in accumbens circuit function.
  • Functional genome-wide short hairpin RNA library screening identifies key molecules for extracellular vesicle secretion from microglia

    • Zhi Ruan,
    • Kayo Takamatsu-Yukawa,
    • Yuzhi Wang,
    • Margaret L. Ushman,
    • Adam Thomas Labadorf,
    • Maria Ericsson,
    • Seiko Ikezu,
    • Tsuneya Ikezu
    Ruan et al. report genome-wide shRNA library screening on a tdTomato-CD63+ microglia cell model to identify factors implicated in the process of extracellular vesicle (EV) release. The molecules Sepp1, Mcfd2, and Sdc1 are critical for ATP-induced secretion of EV and EV-associated interleukin-1β from murine microglia.
  • SETD4-mediated KU70 methylation suppresses apoptosis

    • Yuan Wang,
    • Bochao Liu,
    • Huimei Lu,
    • Jingmei Liu,
    • Peter J. Romanienko,
    • Gaetano T. Montelione,
    • Zhiyuan Shen
    Wang et al. identify the methylation of mammalian KU70 by SETD4. This posttranslational modification is critical for KU70 localization to the cytoplasm and subsequent suppression of apoptosis.


  • A pan-cancer metabolic atlas of the tumor microenvironment

    • Neha Rohatgi,
    • Umesh Ghoshdastider,
    • Probhonjon Baruah,
    • Tanmay Kulshrestha,
    • Anders Jacobsen Skanderup
    Rohatgi et al. profile the metabolic phenotypes of cancer and stromal/immune cells across 20 tumor types, identifying cancer- and stromal-cell-specific metabolic pathways. They find recurrent upregulation of oxidative phosphorylation in cancer cells, which suggests that the Warburg effect may be less pronounced in cancer cells in vivo.
  • Reduced housing density improves statistical power of murine gut microbiota studies

    • Amber Russell,
    • Joanna N. Copio,
    • Yushu Shi,
    • Sumin Kang,
    • Craig L. Franklin,
    • Aaron C. Ericsson
    Cage effects are a broad concern in mouse microbiome studies, given close contact and coprophagic behaviors. By comparing housing densities, Russell et al. show that reduced housing density consistently results in reduced cage effects and increased statistical power to detect antibiotic treatment-associated effects in the gut microbiome, despite comparable susceptibilities.