Heran Darwin Lab - Microbiology

 

Heran Darwin PhD
Professor, Department of Microbiology
Alexandria Center for Life Science – West Tower
430 East 29th Street
Lab Rm. 324, Office Rm. 312
New York, NY 10016
Office: (212) 263-2624
Lab: (212) 263-2626
Email: heran.darwin@nyulangone.org

 

 

KEY INTERESTS:

Mycobacterium tuberculosis, microbial pathogenesis; molecular biology; proteasome, pupylation, Pup, copper, transcriptional regulation, proteolysis.

BIOGRAPHIC DETAILS:

Graduate Education:

1992-1999 PhD, University of California, Los Angeles

Postdoctoral Training:

1999-2001: Washington University, School of Medicine
2001-2003: Weill Medical College of Cornell University

Academic Appointments:

2004: Assistant Professor of Microbiology
2009: Associate Professor of Microbiology

Major Responsibilities:

Course Director (Advanced Topics in Microbial Pathogenesis)
Member of the NIH Bacterial Pathogenesis study section (2011-2015)

Major Honors:

ICAAC Young Investigator Award (2006)
Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases (2009)
Irma T Hirschl Award Recipient (2010)
Kavli Fellow (2012)
American Academy of Microbiology fellow (2016)

RESEARCH INTERESTS:

THE MYCOBACTERIUM TUBERCULOSIS PROTEASOME AND PATHOGENESIS

The pathogen and the disease. Tuberculosis is one of the leading causes of death in the world, killing about 2 million people per year. Nearly one-third of the world is infected with Mtb, which is a rod-shaped bacterium that persists naturally only in human lungs. Although healthy individuals usually control Mtb growth, immunosuppression due to a variety of causes can result in increased bacterial replication and the onset of symptoms. Antibiotic therapy is prolonged (6-9 months) and the failure to comply with treatment can lead to the development of multi-drug and extensively drug resistant strains. New drugs to treat tuberculosis are urgently needed, thus researchers are working to identify activities in Mtb that can be targeted.

The task of finding new drugs and drug targets is hindered by the fact that Mtb is dangerous and slow growing, requiring 2-3 weeks to form colonies on solid media. Furthermore, due to the highly infectious nature of the pathogen, all work must be performed in a biosafety level-3 facility. Taken together, Mtb is one of the most significant and challenging organisms to study.

Mycobacterial resistance to host defenses: the bacterial proteasome and pupylation. Mtb proteasome activity is required for nitric oxide (NO)-resistance and virulence in mice, linking protein degradation to host defense and pathogenesis. ATP-dependent proteolysis by the Mtb proteasome requires a 20S proteasome core particle, Pup (prokaryotic ubiquitin-like protein), Mpa (Mycobacterium proteasomal ATPase), PafA (proteasome accessory factor A), and Dop (deamidase of Pup). The 20S core particle is a barrel shaped chamber with protease activity while Mpa forms hexamers with ATPase activity and caps the base of the 20S core particle to facilitate protein unfolding and degradation. Pup is a post-translational modifier (the first to be identified in prokaryotes) and allows proteins to be targeted for proteasomal degradation by Mpa. Dop and PafA are required for the conjugation of Pup to proteins to target them to the proteasome. Importantly, mutants that cannot pupylate or degrade pupylated proteins are highly attenuated for virulence in mice.

ATP-independent protein degradation. In addition to degrading pupylated proteins, we found Mtb encodes a second proteasome activator called PafE (also known as Bpa). PafE forms unprecedented dodecameric rings without ATPase activity, yet robustly promotes the degradation of specific proteins in Mtb, including the regulator of a major protein quality control system. Importantly, like Mpa and pupylation, PafE is also required for the full virulence of Mtb.

Proteasomal regulation of virulence. Over the years we have worked to understand how protein degradation by a proteasome promotes Mtb pathogenesis. Because the Mtb proteasome can degrade potentially hundreds of different proteins, there are likely to be numerous answers to this question. A key function of the Mpa-proteasome is to degrade the enzyme Lonely guy or Log. Log synthesizes molecules known as cytokinins, the breakdown of which results in the production of aldehydes. Aldehydes are toxic and we found Mtb is particularly sensitive to different aldehydes, especially in the presence of NO. In addition to understanding how cytokinin-derived aldehydes are toxic to Mtb, we are also working to identify a cytokinin-signaling pathway in Mtb, which would represent the first one to be characterized in prokaryotes.

Questions we are currently working to answer:

(a) How are proteins targeted for pupylation?

(b) How are pupylated proteins targeted to the Mpa-proteasome?

(c) How are proteins recognized by the PafE-proteasome?

(d) How do cytokinins transduce signals in Mtb?

(e) How do aldehydes and NO synergize to kill Mtb?

CLICK TO VIEW DR. HERAN DARWIN'S PUBLICATIONS

LAB MEMBERS:

Edward Ballister, PhD
Samuel Becker
Amber Cornelius
Ashley Jordan
Shoshanna Kahne

ALUMNI: 

Susan Zhang
Mike Pearce, PhD
Ricky Festa, PhD
Susan Butler-Wu, PhD
Daniel Sinsimer, PhD
Francisca Cerda-Maira, PhD
Kristin Burns, PhD
Xiaoshan "Shirely" Shi, PhD
Jordan Jastrab, PhD
Marie Samanovic-Golden, PhD

Click here for Heran Darwin's thoughts on the proteasome, basic science, and mentorship, on Toshiki Nakashige's Scientist podcast.

Day Bowling 2018:

2018 Gordon Research Conference on Microbial Toxins & Pathogenicity:


(Pictured: Drs. Andrew Darwin, Victor Torres, and Heran Darwin)

Darwin Lab Circa 2017:

When an artist and a scientist meet…

Performance Art Proteasome