Mechanisms of disease

  • Article
    | Open Access

    The endolysosomal pathway plays an important role in regulating protein and lipid sorting and degradation. Here, the authors show that TMEM16K, an endoplasmic reticulum lipid scramblase, forms ER-endosome contact sites where it regulates endosomal sorting.

    • Maja Petkovic
    • , Juan Oses-Prieto
    •  & Yuh Nung Jan
  • Article
    | Open Access

    The majority of high grade serous ovarian cancers originate from fallopian tube secretory epithelial cells (FTSECs). Here the authors show that miR-181a drives oncogenic transformation in FTSECs through the cooperative inhibition of the tumor suppressor RB1 and of STING, resulting in genomic instability and suppression of intrinsic interferon signaling.

    • Matthew Knarr
    • , Rita A. Avelar
    •  & Analisa DiFeo
  • Article
    | Open Access

    Retinal vein occlusion can cause blindness, and features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here the authors report a non-apoptotic role of endothelial caspase-9 in regulating blood-retina barrier integrity and neuronal survival, which can be therapeutically targeted in a mouse model of retinal vein occlusion.

    • Maria I. Avrutsky
    • , Crystal Colón Ortiz
    •  & Carol M. Troy
  • Article
    | Open Access

    Anorexia nervosa is an eating disorder characterized by fear of gaining weight that can lead to serious complications. Here the authors show that inhibition of SIRT1 is protective against the onset and progression of anorectic behavior in an activity-based anorexia model, suggesting SIRT1 could be a potential therapeutic target.

    • Timothy M. Robinette
    • , Justin W. Nicholatos
    •  & Sergiy Libert
  • Article
    | Open Access

    The DIS3L2 exonuclease degrades aberrant 7SL RNAs tagged by an oligouridine 3′-tail. Here the authors analyze DIS3L2 knockout mouse embryonic stem cells and suggest that DIS3L2-mediated quality control of 7SL RNA is important for ER-mediated translation and calcium ion homeostasis.

    • Mehdi Pirouz
    • , Chih-Hao Wang
    •  & Richard I. Gregory
  • Article
    | Open Access

    The relationship between histopathology, gene expression, and biochemical and mechanical properties of wounds is largely unknown. Here, the authors show that activin A alters wound healing at multiple levels by promoting pro-fibrotic gene expression and matrix deposition, thereby affecting biomechanical properties of skin wounds.

    • Mateusz S. Wietecha
    • , Marco Pensalfini
    •  & Sabine Werner
  • Article
    | Open Access

    During the progression of type 2 diabetes, insulin-producing β-cells can lose their identity and become reprogrammed into other cell types. Here the authors show that murine diabetic β-cells require the protein Raptor for maintaining β-cell health and preventing them from turning into α-cells, independent of Raptor’s involvement in regulating blood sugar levels.

    • Qinglei Yin
    • , Qicheng Ni
    •  & Guang Ning
  • Article
    | Open Access

    Chronic lung diseases are characterized by molecular and cellular composition changes. Here the authors use single-cell RNA sequencing to map cell type-specific changes in human tracheal epithelium related to smoking, and to provide evidence for a tuft-like progenitor for pulmonary neuroendocrine cells and ionocytes.

    • Katherine C. Goldfarbmuren
    • , Nathan D. Jackson
    •  & Max A. Seibold
  • Article
    | Open Access

    Progressive fibrosis is a driver of morbidity and mortality in many chronic liver diseases, but the underlying mechanisms are incompletely understood. Here, the authors show that mitochondria-derived damage-associated molecular patterns are released from injured hepatocytes and can trigger fibrogenic activation of hepatic stellate cells.

    • Ping An
    • , Lin-Lin Wei
    •  & Yury V. Popov
  • Article
    | Open Access

    Macrophages undergo a Warburg-like switch from oxidative phosphorylation to glycolysis in response to inflammatory stimulus. Here the authors show that fungal melanin can trigger this switch in human macrophages by sequestering calcium in the phagosome and enabling protection against Aspergillus fumigatus infection.

    • Samuel M. Gonçalves
    • , Cláudio Duarte-Oliveira
    •  & Agostinho Carvalho
  • Article
    | Open Access

    The origin of the heterogeneity of metabolic and inflammatory profiles exhibited by white adipocytes is little understood. Here, using scRNA-seq and computational methods, the authors show that differentiating preadipocytes exhibit gene expression differences and suggest underlying regulators.

    • Alfred K. Ramirez
    • , Simon N. Dankel
    •  & Simon Kasif
  • Article
    | Open Access

    Adenovirus (AdV) can cause persistent infections, but underlying mechanisms are poorly understood. Here, Prasad et al. show that the AdV glycoprotein E3-19K activates the unfolded protein response sensor IRE1α, and that this triggers a feedforward loop that sustains persistent infection in the presence of interferon.

    • Vibhu Prasad
    • , Maarit Suomalainen
    •  & Urs F. Greber
  • Article
    | Open Access

    Glucagon is elevated Type-2 diabetes, which contributes to poor glucose control in patients with the disease. Here the authors report that secretion of the hormone is controlled by paracrine inhibition, and that resistance of α-cells to somatostatin can explain hyperglucagonemia in type-2 diabetes.

    • Muhmmad Omar-Hmeadi
    • , Per-Eric Lund
    •  & Sebastian Barg
  • Article
    | Open Access

    Small open reading frame-encoded peptides (SEPs), shorter than 100 amino acids, are involved in many cell biological processes. Here the authors identify 16 nuclear-encoded mitochondrial SEPs, including BRAWNIN, an essential regulator of respiratory chain complex III assembly and ATP production.

    • Shan Zhang
    • , Boris Reljić
    •  & Lena Ho
  • Article
    | Open Access

    The transcription factor SREBP is a well-studied and major regulator of sterol and fatty acid metabolism. Here, the authors used haploid genetic screens to identify the Golgi-resident protein SPRING as a new modulator of SREBP by regulating the level of functional SREBP cleavage-activating protein (SCAP).

    • Anke Loregger
    • , Matthijs Raaben
    •  & Noam Zelcer
  • Article
    | Open Access

    It is not yet clear how ubiquitously-expressed proteins can cause the selective degeneration of particular populations of neurons, such as in spinocerebellar ataxia type 17, SCA17, which results from a CAG trinucleotide repeat expansion in the ubiquitously expressed transcription factor TBP. Here, the authors show that mutant TBP suppresses the cerebellum-enriched transcription of Inpp5a and link altered levels of INPP5A to the selective degeneration of cerebellar neurons.

    • Qiong Liu
    • , Shanshan Huang
    •  & Shihua Li
  • Article
    | Open Access

    Methylmalonic acidemia is an inherited metabolic disease caused by loss or mutation of the enzyme MMUT. Here the authors use cell and animal models to show that MMUT mutations lead to defective mitophagy and stress in kidney cells, contributing to the pathogenesis in methylmalonic acidemia patients.

    • Alessandro Luciani
    • , Anke Schumann
    •  & Olivier Devuyst
  • Article
    | Open Access

    Metastatic cells can mimic many of the phenotypic behaviors of embryonic cells. Here, the authors generate a melanoblast-specific transcriptome using a genetically engineered mouse model and identify KDELR3 as a pro-metastasis gene in melanoma.

    • Kerrie L. Marie
    • , Antonella Sassano
    •  & Pravin J. Mishra
  • Article
    | Open Access

    Iron metabolism is linked to type 2 diabetes. Here the authors describe a mechanism through which cellular iron deficiency caused by loss of Irp2 impairs Cdkal1 function, resulting in inaccurate proinsulin translation, impaired proinsulin processing and reduced insulin secretion.

    • Maria C. Ferreira dos Santos
    • , Cole P. Anderson
    •  & Elizabeth A. Leibold
  • Article
    | Open Access

    Manipulation of Toll-like receptors (TLRs) affects HIV-1 infection and latency reversal. Here, the authors show that HIV-1 is endocytosed and recognized by TLR8 in human primary CD4+T cells and that TLR8 stimulation induces an inflammatory response that promotes HIV-1 replication and reversal of latency.

    • Hany Zekaria Meås
    • , Markus Haug
    •  & Trude Helen Flo
  • Article
    | Open Access

    UVRAG is involved in autophagy, which loses its tumour suppressor functions when in its truncated form in cancers. Here, the authors use a mouse model that inducibly express this truncated protein and show impaired autophagy, enhanced inflammation and β-catenin stabilisation, which promotes spontaneous tumorigenesis.

    • Christine Quach
    • , Ying Song
    •  & Chengyu Liang
  • Article
    | Open Access

    Most cases of autosomal dominant polycystic kidney disease (ADPKD) are due to mutations in PKD1. Here, Tsukiyama et al. generate monkeys with mutations in PKD1 and show that animals recapitulate key pathological features of the human disease, suggesting these may provide insights into ADPKD pathogenesis and contribute to the development of future therapeutic strategies.

    • Tomoyuki Tsukiyama
    • , Kenichi Kobayashi
    •  & Masatsugu Ema
  • Article
    | Open Access

    Pre-malignant cells harbouring oncogenic mutations can populate and spread throughout a tissue. Here, using a rainbow mouse system, the authors explore how clonal expansion in the mouse intestine might explain high levels of intra-tumoural heterogeneity observed in the disease.

    • Peter G. Boone
    • , Lauren K. Rochelle
    •  & Joshua C. Snyder
  • Article
    | Open Access

    Type 1 as well as type 2 diabetes are characterized by a loss of insulin-producing β-cells. Here the authors show that the FDA-approved drug neratinib has beneficial effects on β-cell survival, insulin secretion, and glycemic control in mouse models of diabetes.

    • Amin Ardestani
    • , Sijia Li
    •  & Kathrin Maedler
  • Article
    | Open Access

    Activated hepatic stellate cells of putative mesodermal origin orchestrate scarring during injury. Here, the authors define a discrete morphologically plastic lineage of embryonic mesothelial-derived scar-orchestrating cells, through a distinct quiescent adult precursor, defined and paradoxically inhibited by WT1.

    • Timothy James Kendall
    • , Catherine Mary Duff
    •  & Nicholas Dixon Hastie
  • Article
    | Open Access

    Mutations in the gene HADHA result in mitochondrial tri-functional protein (MTP) deficiency and can result in sudden infant death syndrome for which there is no treatment. Here the authors show that the MTP deficient pathology in human cardiomyocytes leads to an abnormal cardiolipin pattern and suggests that cardiolipin affecting compounds may serve as a potential therapy.

    • Jason W. Miklas
    • , Elisa Clark
    •  & Hannele Ruohola-Baker
  • Article
    | Open Access

    Arctigenin (ATG) is the major active component of a Chinese herbal remedy known to reduce proteinuria in patients with diabetic kidney disease (DKD). Here, Zhong et al. identify PP2A as a pharmacological target of ATG in podocytes, and find that PP2A is responsible for some of the beneficial effects of ATG in mouse models of DKD.

    • Yifei Zhong
    • , Kyung Lee
    •  & Ruijie Liu
  • Article
    | Open Access

    The identification of synthetic essential genes of PTEN is of therapeutic potential for PTEN-deficient prostate cancers. Here, the authors show that ARID4B is a synthetic essential gene in these cancers in which deficiency of PTEN prompts the AKT-ARID4B feedback loop required for activation of the PI3K-AKT signaling pathway.

    • Ray-Chang Wu
    • , In-Chi Young
    •  & Mei-Yi Wu
  • Article
    | Open Access

    Stress kinases are activated in peripheral ischemic tissues in the presence of vascular diseases. Here the authors show that inhibition of the neural JNK3 kinase improves recovery from hind limb ischemia in animals through activation of the transcription factors Egr1/Creb1 and upregulation of growth factors.

    • Shashi Kant
    • , Siobhan M. Craige
    •  & John F. Keaney Jr.
  • Article
    | Open Access

    TDP43 aggregates are a hallmark of amyotrophic lateral sclerosis. By using deep mutagenesis to measure the toxicity of more than 50,000 mutations in the prion domain of TDP43, the authors conclude that mutations that increase toxicity promote formation of liquid-like condensates, while aggregation of TDP43 is protective for the cell.

    • Benedetta Bolognesi
    • , Andre J. Faure
    •  & Ben Lehner
  • Article
    | Open Access

    Here, the authors show that reticulocytes derived from immortalized erythroblasts support invasion and development of Plasmodium falciparum and use CRISPR-mediated gene knockout and complementation of an invasion receptor to demonstrate utility of this model system for research in malaria invasion.

    • Timothy J. Satchwell
    • , Katherine E. Wright
    •  & Jake Baum
  • Article
    | Open Access

    Genes related to lysosomal and autophagic systems are transcriptionally regulated by the Mit/TFE family of transcription factors. Here the authors show that MYC, in association with HDACs, suppresses the expression of lysosomal and autophagy genes by competing with the Mit/TFE transcription factors for occupancy of their target gene promoters.

    • Ida Annunziata
    • , Diantha van de Vlekkert
    •  & Alessandra d’Azzo
  • Article
    | Open Access

    In both focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN), kidney injury is characterised by the invasion of glomerular tufts by parietal epithelial cells (PECs). Here Lazareth et al. identify the tetraspanin CD9 as a key regulator of PEC migration, and find its upregulation in FSGS and CGN contributes to kidney injury in both diseases.

    • Hélène Lazareth
    • , Carole Henique
    •  & Pierre-Louis Tharaux
  • Article
    | Open Access

    In the ovary, follicular degeneration occurs after folliculogenesis, with one dominant follicle reaching maturity every month. Here, by performing single cell RNA-seq of adult human follicles, the authors identify subclasses of granulosa and theca cell lineages, which correlate with the growth or degeneration of the follicles.

    • X. Fan
    • , M. Bialecka
    •  & S. M. Chuva de Sousa Lopes
  • Article
    | Open Access

    Cerebral cavernous malformation is a vascular disease characterized by capillary-venous cavernomas in the central nervous system. Here the authors show that cavernomas display benign tumor characteristics and originate from the clonal expansion of mutated endothelial progenitors which can attract surrounding wild-type cells, inducing their mesenchymal transition and leading to growth of the cavernoma.

    • Matteo Malinverno
    • , Claudio Maderna
    •  & Elisabetta Dejana