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Deguine J.,University of California at Berkeley | Wei J.,University of California at Berkeley | Barbalat R.,University of California at Berkeley | Barbalat R.,Nurix Inc | And 2 more authors.
Journal of Immunology | Year: 2017

Neutrophils are generally the first immune cells recruited during the development of sterile or microbial inflammation. As these cells express many innate immune receptors with the potential to directly recognize microbial or endogenous signals, we set out to assess whether their functions are locally influenced by the signals present at the onset of inflammation. Using a mouse model of peritonitis, we demonstrate that neutrophils elicited in the presence of C-type lectin receptor ligands have an increased ability to produce cytokines, chemokines, and lipid mediators in response to subsequent TLR stimulation. Importantly, we found that licensing of cytokine production was mediated by paracrine TNF-α-TNFR1 signaling rather than direct ligand sensing, suggesting a form of quorum sensing among neutrophils. Mechanistically, licensing was largely imparted by changes in the posttranscriptional regulation of inflammatory cytokines, whereas production of IL-10 was regulated at the transcriptional level. Altogether, our data suggest that neutrophils rapidly adapt their functions to the local inflammatory milieu. These phenotypic changes may promote rapid neutrophil recruitment in the presence of pathogens but limit inflammation in their absence. Copyright © 2017 by The American Association of Immunologists, Inc.


Ding Y.,Fred Hutchinson Cancer Research Center | Ding Y.,Novartis | Herman J.A.,Fred Hutchinson Cancer Research Center | Toledo C.M.,Fred Hutchinson Cancer Research Center | And 11 more authors.
Oncotarget | Year: 2017

Zinc finger domain genes comprise ~3% of the human genome, yet many of their functions remain unknown. Here we investigated roles for the vertebratespecific BTB domain zinc finger gene ZNF131 in the context of human brain tumors. We report that ZNF131 is broadly required for Glioblastoma stem-like cell (GSC) viability, but dispensable for neural progenitor cell (NPC) viability. Examination of gene expression changes after ZNF131 knockdown (kd) revealed that ZNF131 activity notably promotes expression of Joubert Syndrome ciliopathy genes, including KIF7, NPHP1, and TMEM237, as well as HAUS5, a component of Augmin/HAUS complex that facilitates microtubule nucleation along the mitotic spindle. Of these genes only kd of HAUS5 displayed GSC-specific viability loss. Critically, HAUS5 ectopic expression was sufficient to suppress viability defects of ZNF131 kd cells. Moreover, ZNF131 and HAUS5 kd phenocopied each other in GSCs, each causing: mitotic arrest, centrosome fragmentation, loss of Augmin/HAUS complex on the mitotic spindle, and loss of GSC self-renewal and tumor formation capacity. In control NPCs, we observed centrosome fragmentation and lethality only when HAUS5 kd was combined with kd of HAUS2 or HAUS4, demonstrating that the complex is essential in NPCs, but that GSCs have heightened requirement. Our results suggest that GSCs differentially rely on ZNF131-dependent expression of HAUS5 as well as the Augmin/HAUS complex activity to maintain the integrity of centrosome function and viability. © Ding et al.


Robertson R.M.,St Jude Childrens Research Hospital | Robertson R.M.,Washington Technology | Yao J.,St Jude Childrens Research Hospital | Gajewski S.,St Jude Childrens Research Hospital | And 5 more authors.
Nature Structural and Molecular Biology | Year: 2017

Phosphatidic acid (PA), the central intermediate in membrane phospholipid synthesis, is generated by two acyltransferases in a pathway conserved in all life forms. The second step in this pathway is catalyzed by 1-acyl-sn-glycerol-3-phosphate acyltransferase, called PlsC in bacteria. Here we present the crystal structure of PlsC from Thermotoga maritima, revealing an unusual hydrophobic/aromatic N-terminal two-helix motif linked to an acyltransferase αβ-domain that contains the catalytic HX 4 D motif. PlsC dictates the acyl chain composition of the 2-position of phospholipids, and the acyl chain selectivity 'ruler' is an appropriately placed and closed hydrophobic tunnel. We confirmed this by site-directed mutagenesis and membrane composition analysis of Escherichia coli cells that expressed mutant PlsC. Molecular dynamics (MD) simulations showed that the two-helix motif represents a novel substructure that firmly anchors the protein to one leaflet of the membrane. This binding mode allows the PlsC active site to acylate lysophospholipids within the membrane bilayer by using soluble acyl donors. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.


Taherbhoy A.M.,Genentech | Taherbhoy A.M.,Nurix Inc | Huang O.W.,Genentech | Cochran A.G.,Genentech
Nature Communications | Year: 2015

Polycomb repressive complex 1 (PRC1) is required for ubiquitination of histone H2A lysine 119, an epigenetic mark associated with repression of genes important in developmental regulation. The E3 ligase activity of PRC1 resides in the RING1A/B subunit when paired with one of six PCGF partners. The best known of these is the oncogene BMI1/PCGF4. We find that canonical PRC1 E3 ligases such as PCGF4-RING1B have intrinsically very low enzymatic activity compared with non-canonical PRC1 RING dimers. The structure of a high-activity variant in complex with E2 (PCGF5-RING1B-UbcH5c) reveals only subtle differences from an earlier PCGF4 complex structure. However, two charged residues present in the modelled interface with E2-conjugated ubiquitin prove critical: in BMI1/PCGF4, these residues form a salt bridge that may limit efficient ubiquitin transfer. The intrinsically low activity of the PCGF4-RING1B heterodimer is offset by a relatively favourable interaction with nucleosome substrates, resulting in an efficient site-specific monoubiquitination. © 2015 Macmillan Publishers Limited. All rights reserved.


News Article | December 6, 2016
Site: www.businesswire.com

SAN FRANCISCO--(BUSINESS WIRE)--Nurix, Inc., a private drug discovery company, today announced the appointment of Dr. Robert Tjian to the company’s board of directors. Dr. Tjian is a member of the National Academy of Sciences and has received numerous awards including the Alfred P. Sloan Prize and the Louisa Gross Horwitz Prize. He was a co-founder of Tularik with Dave Goeddel and Steve McKnight and most recently served as president of the Howard Hughes Medical Institute (HHMI) from 2009 to 2016. After leaving HHMI, Dr. Tjian joined The Column Group as a discovery partner in September 2016. “It is indeed a privilege to welcome Dr. Tjian to the Nurix board of directors,” said Arthur T. Sands, M.D., Ph.D., chief executive officer of Nurix. “Dr. Tjian’s unique combination of scientific expertise and biotechnology business insight will be of great value to Nurix as we translate our breakthrough science into breakthrough drugs for patients.” Dr. Tjian discovered the first transcription factors, human proteins that bind to specific sections of DNA and play a critical role in regulating how genetic information is expressed into the thousands of biomolecules that keep cells, tissues and organisms alive. Dr. Tjian's laboratory has focused on disruptions in the process of transcription that cause diseases such as cancer, metabolic syndromes and neuro-degenerative diseases. In recent years, much of Dr. Tjian’s research has focused on key transcription events in embryonic stem cells. He joined the University of California, Berkeley faculty in 1979, where he assumed several leadership roles including director of the Berkeley Stem Cell Center, faculty director of the Li Ka Shing Center for Biomedical and Health Sciences, and head of the Siebel Stem Initiative. He currently serves as scientific advisor to the Chan Zuckerberg Initiative and the BioHub, and continues to serve on the faculty of the University of California, Berkeley. With his appointment, Dr. Tjian will assume the board seat previously occupied by David Goeddel, Ph.D. of The Column Group. “Dave has made significant contributions to Nurix since its inception and has been a guiding influence for the advancement of Nurix’s scientific and business initiatives, said Dr. Sands. “He has successfully established the company as a leader in the protein homeostasis field and we thank him for his leadership.” Nurix, Inc. is a leader in the discovery of small molecules that modulate the ubiquitin proteasome system (UPS) to address significant, unmet medical needs. The UPS is a regulatory pathway that controls protein levels, a function vital to the healthy life of a cell, and presents therapeutic opportunities in multiple disease areas. Nurix was founded by internationally-recognized experts in the ubiquitin proteasome field and is funded by leading life science investors, Third Rock Ventures and The Column Group. In September 2015, Nurix and Celgene entered into a broad collaboration targeting protein homeostasis for next-generation therapies in oncology, inflammation and immunology. The company is headquartered in San Francisco, California. For more information, please visit www.nurix-inc.com.


Barsanti P.A.,Novartis | Barsanti P.A.,Nurix Inc | Aversa R.J.,Novartis | Jin X.,Novartis | And 13 more authors.
ACS Medicinal Chemistry Letters | Year: 2015

A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series. (Chemical Equation Presented). © 2014 American Chemical Society.


Lebel P.,Stanford University | Basu A.,Stanford University | Basu A.,Howard Hughes Medical Institute | Oberstrass F.C.,Stanford University | And 3 more authors.
Nature Methods | Year: 2014

Single-molecule measurements of DNA twist and extension have been used to reveal physical properties of the double helix and to characterize structural dynamics and mechanochemistry in nucleoprotein complexes. However, the spatiotemporal resolution of twist measurements has been limited by the use of angular probes with high rotational drag, which prevents detection of short-lived intermediates or small angular steps. We introduce gold rotor bead tracking (AuRBT), which yields >100× improvement in time resolution over previous techniques. AuRBT employs gold nanoparticles as bright low-drag rotational and extensional probes, which are monitored by instrumentation that combines magnetic tweezers with objective-side evanescent darkfield microscopy. Our analysis of high-speed structural dynamics of DNA gyrase using AuRBT revealed an unanticipated transient intermediate. AuRBT also enables direct measurements of DNA torque with >50× shorter integration times than previous techniques; we demonstrated high-resolution torque spectroscopy by mapping the conformational landscape of a Z-forming DNA sequence. © 2014 Nature America, Inc. All rights reserved.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2013

DESCRIPTION (provided by applicant): ZAP-70 is a cytoplasmic protein tyrosine kinase that plays a critical function in T cell antigen receptor (TCR) signaling and in most aspects of T cell biology. ZAP-70 is an attractive therapeutic target for treatment of prevalent human T-cell dependent autoimmune diseases (e.g. rheumatoid arthritis, lupus, multiple sclerosis, psoriasis) and in allogenic transplantation. Considerable effort has previously been expended to develop specific ZAP-70 catalytic site inhibitors, without success, likely due to specific structural attributes of the kinase catalytic domain. Following TCR stimulation, the ZAP-70 tandem SH2 domains associate with dual tyrosine phosphorylated residues located within conserved sequence motifs (referredto as ITAMs) of the cytoplasmic domains of the CD3 and zeta chains of the TCR. Mutagenesis and structural studies on full-length ZAP-70 have shown that, prior to association with the ITAMs, ZAP-70 exists in an autoinhibited conformation in which the tandem SH2 domains stabilize an inactive conformation of the kinase domain. This proposal is built on the effort of the Kuriyan and Weiss labs in an NIAMS-funded 2009 ARRA Grand Opportunity grant to identify small molecules that stabilize the autoinhibitedconformation of ZAP-70 and serve as allosteric inhibitors of the kinase. That successful research program led to development of a series of specific biochemical tools for identifying prototypical allosteric inhibitors of ZAP-70, and is poised to enable a dedicated new drug discovery effort in T cell regulation. In this current proposal, Nurix Inc., an emerging biopharmaceutical company founded by John Kuriyan, Art Weiss and Michael Rape, aims to extend this earlier work by optimizing the potency of allosteric inhibitors of ZAP-70 that could serve as a leads for clinical development of a new T-cell specific immunosuppressant. The program will (i) seek insight into the mode of interaction of these small molecule inhibitors with ZAP-70 using crystallographic and other biophysical techniques to facilitate lead optimization, and (ii) examine the activity of allosteric inhibitor compounds in established models of T cell function. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: ZAP-70, an enzyme involved inintracellular signaling, plays a critical role within T cells and is an attractive therapeutic target for treatment of common human autoimmune diseases (e.g. rheumatoid arthritis, lupus, multiple sclerosis, psoriasis) and for controlling organ rejection intransplantation. This program is aimed at finding potent blockers of ZAP-70 that could serve as a leads for clinical development of a new T-cell specific immunosuppressant with broad therapeutic potential.


PubMed | Nurix Inc and Takeda Cambridge
Type: Journal Article | Journal: PloS one | Year: 2015

SUMOylation is a post-translational ubiquitin-like protein modification pathway that regulates important cellular processes including chromosome structure, kinetochore function, chromosome segregation, nuclear and sub-nuclear organization, transcription and DNA damage repair. There is increasing evidence that the SUMO pathway is dysregulated in cancer, raising the possibility that modulation of this pathway may have therapeutic potential. To investigate the importance of the SUMO pathway in the context of cancer cell proliferation and tumor growth, we applied lentivirus-based short hairpin RNAs (shRNA) to knockdown SUMO pathway genes in human cancer cells. shRNAs for SAE2 and UBC9 reduced SUMO conjugation activity and inhibited proliferation of human cancer cells. To expand upon these observations, we generated doxycycline inducible conditional shRNA cell lines for SAE2 to achieve acute and reversible SAE2 knockdown. Conditional SAE2 knockdown in U2OS and HCT116 cells slowed cell growth in vitro, and SAE2 knockdown induced multiple terminal outcomes including apoptosis, endoreduplication and senescence. Multinucleated cells became senescent and stained positive for the senescence marker, SA- Gal, and displayed elevated levels of p53 and p21. In an attempt to explain these phenotypes, we confirmed that loss of SUMO pathway activity leads to a loss of SUMOylated Topoisomerase II and the appearance of chromatin bridges which can impair proper cytokinesis and lead to multinucleation. Furthermore, knockdown of SAE2 induces disruption of PML nuclear bodies which may further promote apoptosis or senescence. In an in vivo HCT116 xenograft tumor model, conditional SAE2 knockdown strongly impaired tumor growth. These data demonstrate that the SUMO pathway is required for cancer cell proliferation in vitro and tumor growth in vivo, implicating the SUMO pathway as a potential cancer therapeutic target.

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