A5038237574- Autophagy in Disease and Therapy
- Telomeres, Telomerase, and Senescence
- interferon and immune responses
- Epigenetics and DNA Methylation
- Genetics, Aging, and Longevity in Model Organisms
- Acute Myeloid Leukemia Research
- Inflammasome and immune disorders
- DNA Repair Mechanisms
- Cytomegalovirus and herpesvirus research
- CRISPR and Genetic Engineering
- Cellular transport and secretion
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Endoplasmic Reticulum Stress and Disease
- Polyamine Metabolism and Applications
- Immune Response and Inflammation
- Health, Environment, Cognitive Aging
- Cancer Genomics and Diagnostics
- Cancer-related gene regulation
- Sirtuins and Resveratrol in Medicine
- Birth, Development, and Health
- Single-cell and spatial transcriptomics
- Genetics and Neurodevelopmental Disorders
- RNA and protein synthesis mechanisms
- Viral Infections and Vectors
Harvard Stem Cell Institute
2020-2025
Center for Neuroscience and Regenerative Medicine
2023-2025
Harvard University Press
2022-2025
Massachusetts General Hospital
2020-2024
Harvard University
2020-2024
University of Pennsylvania
2013-2023
Boston University
2023
Stony Brook University
2010-2016
Memorial Sloan Kettering Cancer Center
2012
Laboratory of Molecular Genetics
2012
A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although known to play an essential role in yeast, its mammals remains elusive. To elucidate physiological function and determine precise autophagy, we have generated f/f mice, which expression Cre recombinase results a deletion exon 4 frame shift causing 755 887 amino acids Vps34. Acute ablation MEFs upon adenoviral infection diminishment localized generation phosphatidylinositol 3-phosphate blockade both...
Abstract Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP) 1 . Mitochondria are major regulators SASP; however, underlying mechanisms have not been elucidated 2 often essential for apoptosis, cell fate distinct from cellular senescence. During widespread mitochondrial outer membrane permeabilization (MOMP) commits to die 3 Here we find that MOMP occurring in subset mitochondria is feature This...
Cellular senescence is a potent tumor suppressor mechanism but also contributes to aging and aging-related diseases. Senescence characterized by stable cell cycle arrest complex proinflammatory secretome, termed the senescence-associated secretory phenotype (SASP). We recently discovered that cytoplasmic chromatin fragments (CCFs), extruded from nucleus of senescent cells, trigger SASP through activation innate immunity cytosolic DNA sensing cGAS–STING pathway. However, upstream signaling...
Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as part normal tissue homeostasis. However, senescent also accumulate in aged and diseased tissues, contributing to inflammation disease progression. The mechanisms mediating impaired immune-mediated clearance are poorly understood. Here, we report that upregulate checkpoint molecule PD-L1, ligand for PD-1 on cells, which drives...
Oncogene-induced senescence (OIS) and therapy-induced (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory prominently includes an array of cytokines known as senescence-associated secretory phenotype (SASP). Previous observations link transcription-associated methyltransferase oncoprotein MLL1 to DDR, leading us investigate role SASP expression. Our findings reveal direct...
Significance The innate immune system plays a key role in host defense that involves the detection of microbial components and series signaling events lead to production interferons cytokines. Recently, identification mitochondrial antiviral-signaling (MAVS) protein placed mitochondria at forefront response against virus infection. However, how MAVS complex is assembled regulated on outer membrane only partially understood. Here we show tripartite motif 14 (TRIM14) facilitates assembly...
Deficiency of autophagy protein beclin 1 is implicated in tumorigenesis and neurodegenerative diseases, but the molecular mechanism remains elusive. Previous studies showed that Beclin coordinates assembly multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III (PI3K-III) lipid kinase activities regulate at different steps. Recent evidence suggests a function regulating VPS34-mediated trafficking pathways beyond autophagy; however, precise role autophagy-independent...
The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved. Here, we report that activates innate response through cytosolic DNA sensing cGAS-STING pathway. induces cellular level of 2'3'-cGAMP associated with STING activation. cGAS recognizes chromatin shuttled from nucleus as result cell-to-cell fusion upon...
The accumulation of damaged or misfolded proteins, if unresolved, can lead to a detrimental consequence within cells termed proteotoxicity. Since cancerous often display elevated protein synthesis and by-product disposal, inhibition the degradation pathways is an emerging approach for cancer therapy. However, molecular mechanism underlying proteotoxicity remains largely unclear. We show here that proteasomal results in increased oligomerization activation caspase-8 on cytosolic side...
The class III phosphoinositide 3-kinase (PI3K) Vps34 (also known as PIK3C3 in mammals) produces phosphatidylinositol 3-phosphate [PI(3)P] on both early and late endosome membranes to control membrane dynamics. We used Vps34-deficient cells delineate whether has additional roles endocytic trafficking. In Vps34-/- mouse embryonic fibroblasts (MEFs), transferrin recycling EEA1 localization were unaffected despite elevated Rab5-GTP levels. Strikingly, a large increase Rab7-GTP levels, an...
Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 activation (CRISPRa) systems have enabled genetic screens in cultured cell lines to discover and characterize drivers inhibitors of cancer growth. We adapted this system for use vivo assess whether modulating endogenous gene expression levels can result functional outcomes the native environment liver. engineered catalytically dead CRISPR-associated (dCas9)-positive mouse, cyclization...