About

David I. Hirsh, PhD, is a Professor of Biochemistry and Molecular Biophysics at Columbia University Irving Medical Center. He is a member of the Department of Biochemistry and Molecular Biophysics. The page lists his academic appointment but does not provide specific details about his research interests, background, or key contributions. Therefore, no further information about his professional biography is available from the provided text.

Research topics

• Chemistry
• Biology
• Biochemistry
• Cell biology

Selected publications

• Structure of the Regulatory Cytosolic Domain of a Eukaryotic Potassium-Chloride Cotransporter

  Structure · 2020 · 12 citations

  • Cell biology
  • Biology
  • Chemistry
  PublisherOA PDFDOI

• Effects of ALS-associated TANK binding kinase 1 mutations on protein–protein interactions and kinase activity

  Proceedings of the National Academy of Sciences · 2019-11-20 · 52 citations

  articleOpen access

  gene associate with both sporadic and familial amyotrophic lateral sclerosis (ALS). Here, we examine functional defects in 25 missense TBK1 mutations, focusing on kinase activity and protein-protein interactions. We identified kinase domain (KD) mutations that abolish kinase activity or display substrate-specific defects in specific pathways, such as innate immunity and autophagy. By contrast, mutations in the scaffold dimerization domain (SDD) of TBK1 can cause the loss of kinase activity due to structural disruption, despite an intact KD. Familial ALS mutations in ubiquitin-like domain (ULD) or SDD display defects in dimerization; however, a subset retains kinase activity. These observations indicate that TBK1 dimerization is not required for kinase activation. Rather, dimerization seems to increase protein stability and enables efficient kinase-substrate interactions. Our study revealed many aspects of TBK1 activities affected by ALS mutations, highlighting the complexity of disease pathogenicity and providing insights into TBK1 activation mechanism.

  PublisherOA PDFDOI

• Gene Expression during Formation of the Cuticle of Caenorhabditis elegans1

  Current problems in dermatology · 2015-04-20 · 4 citations

  article1st authorCorresponding
  PublisherDOI

• The Epistatic Interrelationships of IL-1, IL-1 Receptor Antagonist, and the Type I IL-1 Receptor

  The Journal of Immunology · 2002-07-01 · 47 citations

  articleOpen accessSenior author

  Mice lacking the gene for the IL-1R antagonist (IL-1ra) show abnormal development and homeostasis as well as altered responses to infectious and inflammatory stimuli. A reduction in the level of IL-1 signaling, either by deletion of the receptor or increased expression of IL-1ra, does not affect development or homeostasis, but does alter immune responses. In this study we use genetic epistasis to investigate the interdependence of selected genes in the IL-1 family in the regulation of these developmental and immunological processes. Deletion of the gene encoding the type I IL-1R (IL-1RI) is epistatic to deletion of the IL-1ra gene. Therefore, all functions of IL-1ra depend upon the presence of a functional receptor; there is no other target. Similarly, overexpression of the mRNA encoding the secreted form of IL-1ra is epistatic to deletion of the receptor antagonist, leaving the role of the intracellular splice variants of IL-1ra unknown. The abnormal development of IL-1ra-deficient mice is probably due to chronic overstimulation of the proinflammatory pathway via IL-1, but a clear single pathological defect is not apparent. These results support the model that the only essential function of IL-1ra in both health and disease is competitive inhibition of the IL-1RI.

  PublisherOA PDFDOI

• Distribution and Transport of Cholesterol in<i>Caenorhabditis elegans</i>

  Molecular Biology of the Cell · 2001-06-01 · 181 citations

  articleOpen access

  Cholesterol transport is an essential process in all multicellular organisms. In this study we applied two recently developed approaches to investigate the distribution and molecular mechanisms of cholesterol transport in Caenorhabditis elegans. The distribution of cholesterol in living worms was studied by imaging its fluorescent analog, dehydroergosterol, which we applied to the animals by feeding. Dehydroergosterol accumulates primarily in the pharynx, nerve ring, excretory gland cell, and gut of L1-L3 larvae. Later, the bulk of dehydroergosterol accumulates in oocytes and spermatozoa. Males display exceptionally strong labeling of spermatids, which suggests a possible role for cholesterol in sperm development. In a complementary approach, we used a photoactivatable cholesterol analog to identify cholesterol-binding proteins in C. elegans. Three major and several minor proteins were found specifically cross-linked to photocholesterol after UV irradiation. The major proteins were identified as vitellogenins. rme-2 mutants, which lack the vitellogenin receptor, fail to accumulate dehydroergosterol in oocytes and embryos and instead accumulate dehydroergosterol in the body cavity along with vitellogenin. Thus, uptake of cholesterol by C. elegans oocytes occurs via an endocytotic pathway involving yolk proteins. The pathway is a likely evolutionary ancestor of mammalian cholesterol transport.

  PublisherOA PDFDOI

• Rme-1 regulates the distribution and function of the endocytic recycling compartment in mammalian cells

  Nature Cell Biology · 2001-05-14 · 261 citations

  article
  PublisherDOI

• RME-8, a Conserved J-Domain Protein, Is Required for Endocytosis in<i>Caenorhabditis elegans</i>

  Molecular Biology of the Cell · 2001-07-01 · 164 citations

  articleOpen accessSenior author

  By genetic analysis of Caenorhabditis elegans mutants defective in yolk uptake, we have identified new molecules functioning in the endocytosis pathway. Here we describe a novel J-domain-containing protein, RME-8, identified by such genetic analysis. RME-8 is required for receptor-mediated endocytosis and fluid-phase endocytosis in various cell types and is essential for C. elegans development and viability. In the macrophage-like coelomocytes, RME-8 localizes to the limiting membrane of large endosomes. Endocytosis markers taken up by the coelomocytes rapidly accumulate in these large RME-8-positive endosomes, concentrate in internal subendosomal structures, and later appear in RME-8-negative lysosomes. rme-8 mutant coelomocytes fail to accumulate visible quantities of endocytosis markers. These observations show that RME-8 functions in endosomal trafficking before the lysosome. RME-8 homologues are found in multicellular organisms from plants to humans but not in the yeast Saccharomyces cerevisiae. These sequence homologies suggest that RME-8 fulfills a conserved function in multicellular organisms.

  PublisherOA PDFDOI

• Evidence that RME-1, a conserved C. elegans EH-domain protein, functions in endocytic recycling

  Nature Cell Biology · 2001-05-14 · 270 citations

  articleSenior author
  PublisherDOI

• Immuno-EM Localization of GFP-tagged Yolk Proteins in <i>C. Elegans</i> Using Microwave Fixation

  Journal of Histochemistry & Cytochemistry · 2001-08-01 · 44 citations

  articleOpen access

  Because of the presence of a low-permeability cuticle covering the animal, fixation of C. elegans tissue for immunoelectron microscopy has proved very difficult. Here we applied a microwave fixation protocol to improve penetration of fixatives before postembedding immunogold labeling. Using this technique, we were able to successfully localize several components of yolk (YP170) trafficking in both wild-type and transgenic strains expressing a vitellogenin::green fluorescent protein fusion (YP170::GFP). Green fluorescent protein (GFP) and its variants are commonly used as markers to localize proteins in transgenic C. elegans using fluorescence microscopy. We have developed a robust method to localize GFP at the EM level. This procedure is applicable to the characterization of transgenic strains in which GFP is used to mark particular proteins or cell types and will undoubtedly be very useful for high-resolution analysis of marked structures.

  PublisherOA PDFDOI

• Caenorhabditis elegans auxilin: a J-domain protein essential for clathrin-mediated endocytosis in vivo

  Nature Cell Biology · 2001-01-18 · 91 citations

  article
  PublisherDOI

Recent grants

• NIH Grant R01GM036318

  NIH · $1.9M · 1991

• NIH Grant R01GM026515

  NIH · $179k · 1986

• NIH Grant R01AI042861

  NIH · $1.7M · 2004

• NIH Grant R01GM037823

  NIH · $2.6M · 1998

Frequent coauthors

• George N. Cox

  Bolder Biotechnology, Inc.

  13 shared

• Dan T. Stinchcomb

  Takeda (United States)

  11 shared

• James M. Kramer

  Northwestern University

  11 shared

• Michael Klass

  8 shared

• Barth D. Grant

  Rutgers, The State University of New Jersey

  7 shared

• Nurit Wolf

  Stanford University

  7 shared

• Nancy L. Greenbaum

  The Graduate Center, CUNY

  6 shared

• Emmet Hirsch

  NorthShore University HealthSystem

  6 shared

Labs

• Columbia University Irving Medical Center Biochemistry and Molecular BiophysicsPI