Heran Darwin

Biosketch / Results /

Heran Darwin, Ph.D.

Professor;
Department of Microbiology (Microbiology )

Contact Info

Address
550 First Avenue
Floor 2 Room 236A
Medical Science Building
New York, NY 10016-6481

212-263-2624
212-263-2624
Heran.Darwin@med.nyu.edu


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Research Summary

Mycobacterium tuberculosis (Mtb) is a leading cause of death, infecting and persisting in nearly one-third of the world's population. It is believed that the immune response to Mtb infection causes much of the disease pathology. Although many people are infected with this bacterium, most do not display signs of disease. However, with the growing population of immunocompromised individuals, due to factors such as HIV infection, and the emergence of multi-drug resistant (MDR) strains of Mtb, the mortality due to tuberculosis is on the rise.

There is little question that Mtb requires many genes for dealing with the defenses of the mammalian immune system. One critical aspect of the immune system that is involved in fighting infection by Mtb is the production of nitric oxide (*NO or NO) by inducible nitric oxide synthase (iNOS/NOS2). NOS2 knock out mice are far more susceptible than isogenic wild type (wt) mice to death by Mtb.  In humans, increasing evidence suggests that NOS2 expression is induced in macrophages from Mtb infected patients when compared to healthy, uninfected subjects. These observations strongly implicate a protective role for NO during a Mtb infection.

NO freely diffuses and can react with other molecules such as superoxide and molecules with cysteine sulfhydryls to produce reactive nitrogen intermediates (RNI). Although the production of NO is clearly required for some protection against Mtb in mice, it is not sufficient to clear the bacteria from the host and even immunocompetent mice eventually die. Because RNI are produced by macrophages, the preferred residence of Mtb during an infection, Mtb has most likely developed mechanisms of resistance to RNI.

In order to identify the mechanisms by which Mtb resist killing by RNI, a genetic screen was performed. In this screen, 10,100 Mtb transposon insertion mutants were tested for their susceptibility to NO generated by acidified sodium nitrite (ASN, pH 5.5). From this library, we identified mutants with transposon insertions in two putative components (Mpa and Paf) of the Mtb proteasome. Proteasomes have been studied intensively in eukaryotic organisms, but little is understood about their function in bacteria. In eukaryotes, proteasomes degrade proteins that are damaged, misfolded or otherwise targeted by the cell for destruction. Proteasomes are essential in eukaryotic cells and are required for functions ranging from cell cycle progression to degradation of oxidized proteins to class I MHC presentation of antigens. Although little is known about the function of proteasomes in prokaryotes, it is likely that they serve some similar functions, such as the degradation of damaged proteins. Furthermore, in the event the function of the proteasome is essential for the survival of Mtb when exposed to a particular stress, the proteasome may prove to be an ideal target for the development of new anti-tuberculosis drugs.

mpa and paf mutants are attenuated, even in immunodeficient (iNOS-/-) mice. This suggests that the mutants have other deficiencies that prevent them from being fully pathogenic. My lab's research will focus on determining the roles of Mpa and Paf on proteasome function, if there are indeed such roles for these proteins. In addition, we are examining the transcriptomes and proteasomes of mutant and wt Mtb with the expectation that they will reveal mechanisms of pathogenesis by Mtb.

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All data from NYU Health Sciences Library Faculty Bibliography — -

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http://hsl.med.nyu.edu/faculty-bibliography-search

The copper-responsive RicR regulon contributes to Mycobacterium tuberculosis virulence
Shi, Xiaoshan; Festa, Richard A; Ioerger, Thomas R; Butler-Wu, Susan; Sacchettini, James C; Darwin, K Heran; Samanovic, Marie I
2014 ;5(1):65-70, MBio
— id: 953442, year: 2014, vol: 5, page: 65, stat: Journal Article,

Mycobacterium tuberculosis proteasomes, pupylation and pathogenesis
Darwin, K H
2013 April 2013;27:-, FASEB journal
— id: 550852, year: 2013, vol: 27, page: , stat: Journal Article,

The Pup-Proteasome System of Mycobacterium tuberculosis
Samanovic, Marie I; Li, Huilin; Darwin, K Heran
2013 ;66:267-295, Sub-cellular biochemistry
— id: 242312, year: 2013, vol: 66, page: 267, stat: Journal Article,

Pupylation: proteasomal targeting by a protein modifier in bacteria
Burns, Kristin E; Darwin, K Heran
2012 ;832:151-160, Methods in molecular biology
— id: 173072, year: 2012, vol: 832, page: 151, stat: Journal Article,

Synthesis and Evaluation of a Selective Fluorogenic Pup Derived Assay Reagent for Dop, a Potential Drug Target in Mycobacterium tuberculosis
Merkx, Remco; Burns, Kristin E; Slobbe, Paul; El Oualid, Farid; El Atmioui, Dris; Darwin, K Heran; Ovaa, Huib
2012 Sep;13(14):2056-2060, Chembiochem : a European journal of chemical biology
— id: 179187, year: 2012, vol: 13, page: 2056, stat: Journal Article,

Copper in microbial pathogenesis: meddling with the metal
Samanovic, Marie I; Ding, Chen; Thiele, Dennis J; Darwin, K Heran
2012 Feb;11(2):106-115, Cell host & microbe
— id: 157483, year: 2012, vol: 11, page: 106, stat: Journal Article,

Reconstitution of the Mycobacterium tuberculosis pupylation pathway in Escherichia coli
Cerda-Maira, Francisca A; McAllister, Fiona; Bode, Nadine J; Burns, Kristin E; Gygi, Steven P; Darwin, K Heran
2011 ;12(8):863-870, EMBO reports
— id: 135563, year: 2011, vol: 12, page: 863, stat: Journal Article,

A novel copper-responsive regulon in Mycobacterium tuberculosis
Festa, Richard A; Jones, Marcus B; Butler-Wu, Susan; Sinsimer, Daniel; Gerads, Russell; Bishai, William R; Peterson, Scott N; Darwin, K Heran
2011 Jan;79(1):133-148, Molecular microbiology
— id: 116213, year: 2011, vol: 79, page: 133, stat: Journal Article,

"Depupylation" of prokaryotic ubiquitin-like protein from mycobacterial proteasome substrates
Burns, Kristin E; Cerda-Maira, Francisca A; Wang, Tao; Li, Huilin; Bishai, William R; Darwin, K Heran
2010 Sep 10;39(5):821-827, Molecular cell
— id: 138125, year: 2010, vol: 39, page: 821, stat: Journal Article,

Pupylation : A Signal for Proteasomal Degradation in Mycobacterium tuberculosis
Burns, Kristin E; Darwin, K Heran
2010 ;54:149-157, Sub-cellular biochemistry
— id: 119237, year: 2010, vol: 54, page: 149, stat: Journal Article,

Pupylation versus ubiquitylation: tagging for proteasome-dependent degradation
Burns, Kristin E; Darwin, K Heran
2010 Apr 1;12(4):424-431, Cellular microbiology
— id: 109512, year: 2010, vol: 12, page: 424, stat: Journal Article,

Prokaryotic ubiquitin-like protein provides a two-part degron to Mycobacterium proteasome substrates
Burns, Kristin E; Pearce, Michael J; Darwin, K Heran
2010 Jun;192(11):2933-2935, Journal of bacteriology
— id: 109670, year: 2010, vol: 192, page: 2933, stat: Journal Article,

Molecular analysis of the prokaryotic ubiquitin-like protein (Pup) conjugation pathway in Mycobacterium tuberculosis
Cerda-Maira, Francisca A; Pearce, Michael J; Fuortes, Michele; Bishai, William R; Hubbard, Stevan R; Darwin, K Heran
2010 Sep;77(5):1123-1135, Molecular microbiology
— id: 114585, year: 2010, vol: 77, page: 1123, stat: Journal Article,

SAMPyling proteins in archaea
Darwin, K Heran; Hofmann, Kay
2010 Jun;35(6):348-351, Trends in biochemical sciences
— id: 110081, year: 2010, vol: 35, page: 348, stat: Journal Article,

Prokayrotic ubiquitin-like protein (Pup) proteome of Mycobacterium tuberculosis
Festa, Richard A; McAllister, Fiona; Pearce, Michael J; Mintseris, Julian; Burns, Kristin E; Gygi, Steven P; Darwin, K Heran
2010 ;5(1):e8589-e8589, PLoS one
— id: 106208, year: 2010, vol: 5, page: e8589, stat: Journal Article,

Binding-induced folding of prokaryotic ubiquitin-like protein on the Mycobacterium proteasomal ATPase targets substrates for degradation
Wang, Tao; Darwin, K Heran; Li, Huilin
2010 Nov;17(11):1352-1357, Nature structural & molecular biology
— id: 133840, year: 2010, vol: 17, page: 1352, stat: Journal Article,

The Mycobacterium tuberculosis Proteasome: More Than Just a Barrel-shaped Protease
Cerda-Maira, Francisca; Darwin, K Heran
2009 Dec;11(14-15):1150-1155, Microbes & infection
— id: 101566, year: 2009, vol: 11, page: 1150, stat: Journal Article,

Prokaryotic Ubiquitin-Like Protein Pup Is Intrinsically Disordered
Chen, Xiang; Solomon, William C; Kang, Yang; Cerda-Maira, Francisca; Darwin, K Heran; Walters, Kylie J
2009 Sep 11;392(1):208-217, Journal of molecular biology
— id: 101567, year: 2009, vol: 392, page: 208, stat: Journal Article,

Prokaryotic ubiquitin-like protein (Pup), proteasomes and pathogenesis
Darwin, K Heran
2009 Jul;7(7):485-491, Nature reviews. Microbiology
— id: 100188, year: 2009, vol: 7, page: 485, stat: Journal Article,

Structural insights on the Mycobacterium tuberculosis proteasomal ATPase Mpa
Wang, Tao; Li, Hua; Lin, Gang; Tang, Chunyan; Li, Dongyang; Nathan, Carl; Darwin, K Heran; Li, Huilin
2009 Oct 14;17(10):1377-1385, Structure
— id: 112096, year: 2009, vol: 17, page: 1377, stat: Journal Article,

Ubiquitin-like protein involved in the proteasome pathway of Mycobacterium tuberculosis
Pearce, Michael J; Mintseris, Julian; Ferreyra, Jessica; Gygi, Steven P; Darwin, K Heran
2008 Nov 14;322(5904):1104-1107, Science
— id: 93375, year: 2008, vol: 322, page: 1104, stat: Journal Article,

Characterization of the proteasome accessory factor (paf) operon in Mycobacterium tuberculosis
Festa, Richard A; Pearce, Michael J; Darwin, K Heran
2007 Apr;189(8):3044-3050, Journal of bacteriology
— id: 72728, year: 2007, vol: 189, page: 3044, stat: Journal Article,

Self-compartmentalized bacterial proteases and pathogenesis
Butler, Susan M; Festa, Richard A; Pearce, Michael J; Darwin, K Heran
2006 May;60(3):553-562, Molecular microbiology
— id: 64667, year: 2006, vol: 60, page: 553, stat: Journal Article,

Identification of substrates of the Mycobacterium tuberculosis proteasome
Pearce, Michael J; Arora, Pooja; Festa, Richard A; Butler-Wu, Susan M; Gokhale, Rajesh S; Darwin, K Heran
2006 Nov 15;25(22):5423-5432, EMBO journal
— id: 69696, year: 2006, vol: 25, page: 5423, stat: Journal Article,

Characterization of a Mycobacterium tuberculosis proteasomal ATPase homologue
Darwin, K Heran; Lin, Gang; Chen, Zhiqiang; Li, Huilin; Nathan, Carl F
2005 Jan;55(2):561-571, Molecular microbiology
— id: 56015, year: 2005, vol: 55, page: 561, stat: Journal Article,

Role for nucleotide excision repair in virulence of Mycobacterium tuberculosis
Darwin, K Heran; Nathan, Carl F
2005 Aug;73(8):4581-4587, Infection & immunity
— id: 96290, year: 2005, vol: 73, page: 4581, stat: Journal Article,

A glutamate-alanine-leucine (EAL) domain protein of Salmonella controls bacterial survival in mice, antioxidant defence and killing of macrophages: role of cyclic diGMP
Hisert, Katherine B; MacCoss, Michael; Shiloh, Michael U; Darwin, K Heran; Singh, Shaneen; Jones, Roger A; Ehrt, Sabine; Zhang, Zhaoying; Gaffney, Barbara L; Gandotra, Sheetal; Holden, David W; Murray, Diana; Nathan, Carl
2005 Jun;56(5):1234-1245, Molecular microbiology
— id: 96291, year: 2005, vol: 56, page: 1234, stat: Journal Article,

The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide
Darwin, K Heran; Ehrt, Sabine; Gutierrez-Ramos, Jose-Carlos; Weich, Nadine; Nathan, Carl F
2003 Dec 12;302(5652):1963-1966, Science
— id: 45183, year: 2003, vol: 302, page: 1963, stat: Journal Article,

Type III secretion chaperone-dependent regulation: activation of virulence genes by SicA and InvF in Salmonella typhimurium
Darwin KH; Miller VL
2001 Apr 17;20(8):1850-1862, EMBO journal
— id: 45184, year: 2001, vol: 20, page: 1850, stat: Journal Article,

SigE is a chaperone for the Salmonella enterica serovar Typhimurium invasion protein SigD
Darwin KH; Robinson LS; Miller VL
2001 Feb;183(4):1452-1454, Journal of bacteriology
— id: 45185, year: 2001, vol: 183, page: 1452, stat: Journal Article,

The putative invasion protein chaperone SicA acts together with InvF to activate the expression of Salmonella typhimurium virulence genes
Darwin KH; Miller VL
2000 Feb;35(4):949-960, Molecular microbiology
— id: 45186, year: 2000, vol: 35, page: 949, stat: Journal Article,

InvF is required for expression of genes encoding proteins secreted by the SPI1 type III secretion apparatus in Salmonella typhimurium
Darwin KH; Miller VL
1999 Aug;181(16):4949-4954, Journal of bacteriology
— id: 45187, year: 1999, vol: 181, page: 4949, stat: Journal Article,

Molecular basis of the interaction of Salmonella with the intestinal mucosa
Darwin KH; Miller VL
1999 Jul;12(3):405-428, Clinical microbiology reviews
— id: 45188, year: 1999, vol: 12, page: 405, stat: Journal Article,