Faculty & Staff

Mahak Sharma
Associate Professor
PhD (2009) University of Nebraska Medical Center, Omaha, Nebraska
Room No. 3F7, Academic Block-2
Sector 81
IISER Mohali

Phone: 0172-2293145
Email: msharma[at]iisermohali.ac.in

Mahak Sharma

Research summary


With the advent of compartmentalization in eukaryotic organisms, it became crucial for proteins to traffic to their correct location within the cell and therefore need for constant communication between these compartments. Membrane trafficking is a fundamental process that mediates the directed movement of proteins and membranes between different cellular locations, critical for the proper functioning of all eukaryotic cells. The primary research interests of my laboratory focus on studying the molecular mechanisms regulating the trafficking towards late endosomes and lysosomes. Lysosomes are membrane-bound organelles present in eukaryotes whose catabolic function is essential for maintaining general cellular homeostasis. In my laboratory, we are studying the function of small GTPases and tethering factor complexes that are present on lysosomes and regulate endocytic, phagocytic and autophagic traffic towards lysosomes (see schematic in Figure 1).


The importance of these proteins is reflected by the fact that pathogens such as Mycobacterium.tuberculosis or Salmonella evade killing in the host lysosome by targeting these protein complexes (see Figure 2) figure-2

On the other hand, recent studies have shown that Ebola and Marburg filoviruses that cause rapidly fatal haemorrhagic fever in humans use lysosomal tethering complexes to escape from endosomes and establish infection. Our findings will contribute to a better understanding of the mechanism by which the endocytic regulatory proteins including small GTPases and tethering factors regulates lysosomal trafficking, proper functioning of which is critical for cellular survival and defense against pathogens. Additionally, the proposed studies have practical applications for the development of new therapeutic approaches to induce the clearance of intracellular bacteria and viruses by our cells.

Scientific Questions that we are interested in:

1. To understand the organization and function of mammalian HOPS (HOmotypic fusion and Protein Sorting) complex in regulating trafficking towards lysosomes :

HOPS complex is an evolutionarily conserved six-subunit complex that together regulates trafficking into the vacuole/lysosome. Four of these VPS (vacuole protein sorting) subunits, Vps11, Vps16, Vps18, and Vps33 constitute a core complex termed VPS-C (core), and two additional subunits, Vps39 and Vps41, combine with VPS-C to form the six-subunit HOPS complex.
The HOPS complex is considered to be the critical tethering complex that mediates the fusion of late endosomes and lysosomes. The HOPS complex subunits are conserved from yeast to humans, however, unlike yeast where the function of the HOPS subunits are well characterized in vesicle tethering, not much is known about the mammalian HOPS complex and the mechanism of their action.
In this project, we aim to understand how mammalian HOPS subunits are recruited to late endosomes and lysosomes. Recent work from our laboratory suggests that Arf-like GTPase Arl8b directly binds to and regulates recruitment of human HOPS complex to lysosomal membranes (Khatter et al., Journal of Cell Science 2015, see Figure 3).
Moreover, we are exploring identity of the SNARE proteins that interact with mammalian HOPS subunits, and mediate fusion of late endosomes and lysosomes. Furthermore, we aim to set up an in vitro assay to understand the mechanisms by which HOPS complex regulates tethering and vesicle fusion.

2. To understand the function of HOPS complex in regulating clearance of intracellular bacteria:

Several intracellular pathogens such as Mycobacterium, Legionella, Coxiella and Salmonella hijack the endocytic machinery of the cell for their advantage to establish a replicative niche inside the host cells. While intracellular bacteria like Mycobacterium tuberculosis and Coxiella brunetii prevent/delay phagosome-lysosome fusion to avoid digestion in lysosomes, Salmonella typhimurium resides in a compartment formed by fusion with late endocytic compartments. In this context, we want to study the role of HOPS complex in regulating biogenesis of phagolysosomes containing either Mycobacterium that avoids fusion with lysosomes, or Salmonella that requires fusion with lysosomes, for their survival. We are currently exploring the mechanisms by which HOPS complex mediate formation of the Salmonella-containing vacuole and Salmonella-induced filaments and identification of bacterial effectors that can interact with HOPS subunits (see Figure 2).

3. Characterizing the function of mammalian Hook proteins in organelle motility and vesicular trafficking:

Lysosomes like other cellular organelles move on microtubule tracks with the help of motor proteins such kinesin and dynein. This bi-directional movement not only controls their subcellular distribution but also regulates several of their downstream functions including endocytic degradation. In this context, we are characterizing the function of the mammalian Hook proteins namely Hook1, Hook2 and Hook3. Hook proteins were first discovered in Drosophila and are regarded as linkers between organelles and microtubule cytoskeleton and/or motor proteins. However, thus far the role of mammalian Hooks in regulating organelle distribution/motility and association with motor proteins has not been explored. We are currently investigating the function of Hook proteins on lysosomal subcellular distribution and their interaction with microtubule motors.

Honors and Awards

  • Nominated and elected to Journal of Cell Biology Early Career Advisory Board (ECAB)
  • Nominated to Editorial Board of Traffic Journal
  • Awarded “NASI-Young Scientist Platinum Jubilee Award (2018)”
  • Awarded “INSA Medal for Young Scientist(2018)”
  • Featured by the Life of Science organization “Women in Science” (2018)
  • Selected as a member ofThe Indian National Young Academy of Science (INYAS) (2018)
  • Featured in “Cell Scientist to Watch” column by the Journal of Cell Science (2017)
  • Awarded SERB-Women Excellence Award (2017).
  • Selected as a Young Associate of the Indian Academy of Sciences, Bangalore (July 2015).
  • Co-recipient of IISER-Mohali Best Teacher Award (2015).
  • Selected to the editorial board of “Frontiers in Cell and Development Biology” journal (2014).
  • Awarded with the prestigious “Wellcome Trust/DBT India Alliance Intermediate Fellowship” (April 2012).
  • Recipient of the “Thomas Jefferson Ingenuity Award” for the year 2010, University of Nebraska Medical Center, Omaha, Nebraska, USA. This is a most highly prized award that is given to a single graduating Ph.D. student every year by the University of Nebraska Medical Center. This award recognizes a Ph.D. graduate student who has exhibited unmatched creativity in his/her doctoral research efforts. To be nominated for this award, the student must have an absolutely outstanding record from his/her own department, and then must compete with top applicants from the entire medical school and campus.
  • Featured in NRI Achievers: The Times of India (March 28th 2011) http://timesofindia.indiatimes.com/nri/nri-achievers/Dr-Mahak-Sharma-wins-prestigious-research-award-in-US/articleshow/7807540.cms
  • American Heart Association (AHA) Pre-doctoral Fellowship Recipient (July 2008-June 2010).
  • Recipient of Norman and Bernice Harris Award in Cancer Research (March 2008). This award recognizes an outstanding Ph.D. student who has exhibited the highest degree of caring, creativity, and ingenuity in cancer research.

Selected Publications

  • Devashish Dwivedi, Amrita Kumari, Siddhi Rathi, Sivaram V.S. Mylavarapu and Mahak Sharma*. The dynein adaptor Hook2 plays essential roles in mitotic progression and cytokinesis. Journal of Cell Biology (in press, 2018). *corresponding author
  • Amit Tuli and Mahak Sharma*. How to do business with lysosomes: Salmonella leads the way. Current Opinion in Microbiology, 47:1-7 (2018). *co-corresponding author [invited review].
  • Xavier Michelet, Amit Tuli, Huixian Gan, Carolina Geadas, Mahak Sharma, Heinz G. Remold and Michael B. Brenner. Lysosome-mediated plasma membrane repair is dependent on the small GTPase Arl8b and determines cell death type inMycobacterium tuberculosisinfection.Journal of Immunology, 200(9):3160-3169 (2018).
  • Aastha Sindhwani, Subhash B. Arya, Harmeet Kaur, Divya Jagga, Amit Tuli and Mahak Sharma*. Salmonellaexploits the host endolysosomal tethering factor HOPS complex to promote its intravacuolar replication. *Corresponding author. PLOS Pathogens, 13(10):e1006700. DOI: 10.1371/journal.ppat.1006700 (2017).The findings of this research were covered in various online news media websites including:
  • Rituraj Marwaha and Mahak Sharma*.DQ-Red BSA trafficking assay in cultured cells to assess cargo delivery to lysosomes.*Corresponding author. Bio-protocol,7(19): e2571. DOI: 10.21769/BioProtoc.2571 (2017).
  • Rituraj Marwaha, Subhash B. Arya, Divya Jagga, Harmeet Kaur, Amit Tuli* and Mahak Sharma*. The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes. * corresponding author. Journal of Cell Biology, 216(4):1051-1070 (2017).
  • Divya Khatter, Aastha Sindhwani, and Mahak Sharma*. Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology [review article]. *Corresponding author. Cellular Logistics 5 (3), 2015
  • Divya Khatter, Vivek B. Raina, Devashish Dwivedi, Aastha, Sindhwani, Surbhi Bahl and Mahak Sharma*. The small GTPase Arl8b regulates assembly of the mammalian HOPS complex to lysosomes. *corresponding author. J. Cell Sci., 128(9):1746-1761 (2015). This research article was selected as the “top most read” article for the month of May 2015 by the Journal of Cell Science.
  • Amit Tuli, Jerome Thiery, Ashley M. James, Xavier Michelet, Mahak Sharma, Salil Garg, Keri B. Sanborn, Jordan S. Orange, Judy Lieberman, and Michael B. Brenner. Arf-like GTPase Arl8b regulates lytic granule polarization and natural killer cell–mediated cytotoxicity. Mol. Biol. Cell, 24(23):3721-3735 (2013). This article was featured on the cover of Mol. Biol. Cell December issue.
  • Salil Garg*, Mahak Sharma*, Cindy Ung, Amit Tuli, Duarte C. Barral, David L. Hava, Natacha Veerapen, Gurdyal S. Besra, Nir Hacohen and Michael B. Brenner. Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b. *Equal contribution. Immunity, 35(2):182-193 (2011). This research article was highlighted in the Cell Press published monthly podcasts (September 1, 2011) and was chosen by Faculty of 1000 Biology, an expert guide to the most important advances in biology, and was evaluated as “recommended” with a 7.0 rating.
  • Mahak Sharma, Sai Srinivas Panapakkam Giridharan, Juliati Rahajeng, Naava Naslavsky and Steve Caplan. MICAL-L1: an unusual Rab effector that links EHD1 to tubular recycling endosomes. Article Addendum. Communicative and Integrative Biology, 3(2):1-3 (2010). This article was highlighted as one of the “most popular” downloaded paper by the Communicative and Integrative Biology journal website (April, 2010).
  • Fabien Kieken*, Mahak Sharma*, Marko Jovic*, Sai Srinivas Panapakkam Giridharan, Naava Naslavsky, Steve Caplan and Paul Sorgen. Mechanism for the selective interaction of C-terminal EH-domain proteins with specific NPF-containing partners. *Equal contribution. Journal of Biological Chemistry, 285(12):8687-8694 (2010).
  • Marko Jovic*, Mahak Sharma*, Juliati Rahajeng and Steve Caplan. The early endosome: a busy sorting station for proteins at the crossroads [review]. *Equal contribution. Histology and Histopathology, 25(1):99-112 (2010).
  • Saumya Pant, Mahak Sharma, Kruti Patel, Steve Caplan, Chavela Carr and Barth Grant. AMPH-1/Amyphysin/Bin1 functions with RME-1/Ehd1 in endocytic recycling. Nature Cell Biology, 11(12):1399-1410 (2009).
  • Mahak Sharma, Marko Jovic, Fabien Kieken, Naava Naslavsky, Steve Caplan and Paul Sorgen. A model for the role of EHD1-containing membrane tubules in endocytic recycling. Article Addendum. Communicative and Integrative Biology, 2(5):431-433 (2009).
  • Mahak Sharma, Sai Srinivas Panapakkam Giridharan, Juliati Rahajeng, Naava Naslavsky and Steve Caplan. MICAL-L1 links EHD1 to tubular recycling endosomes and regulates receptor recycling. Molecular Biology of the Cell, 20(24):5181-5194 (2009).
  • Amit Tuli, Mahak Sharma, Haley Capek, Naava Naslavsky, Steve Caplan and Joyce C. Solheim. Mechanism for amyloid precursor-like protein 2 enhancement of major histocompatibility complex class I molecule degradation. Journal of Biological Chemistry, 284(49):34296-34307 (2009). This paper was chosen by Faculty of 1000 Biology and was evaluated as “recommended” with a 6.0 rating.
  • Amit Tuli, Mahak Sharma, Mary M. McIlhaney, James E. Talmadge, Naava Naslavsky, Steve Caplan and Joyce C. Solheim. Amyloid precursor-like protein 2 increases the endocytosis, instability and turnover of the H2-Kd MHC class I molecule. Journal of Immunology, 181(3):1978-1987 (2008).
  • Mahak Sharma, Naava Naslavsky and Steve Caplan. A role for EHD4 in the regulation of early endosomal transport. Traffic, 9(6):995-1018 (2008).


Current Lab Members:

Devashish Dwivedi (PhD student)

Aastha Sindhwani (PhD student)

Rituraj Marwaha (PhD student)

Shalini Rawat (PhD student)

Prateek Chawla (Integrated MS-PhD student)

Dr. Hema Kumari Alajangi (Post-doctoral fellow)

Harmeet Kaur (Project assistant)


  • Divya Khatter (PhD student, 2012-2017); Current Position: Professional Expert, Scientific Communication at THSTI Faridabad, India.
  • Divya Jagga (Project Assistant, 2015-2017); Current Position: Medical Writer at inVentiv International, India
  • Vaishnavi Sridhar (BS-MS student, IISER-Mohali, Batch: 2012-17); Current Position: Ph.D. student at University of British Columbia, Canada
  • Siddhi Rathi (BS-MS student, IISER-Mohali, Batch: 2012-17); Current Position: Ph.D. student at University of Melbourne, Australia
  • Shambhu Yadav (Project Assistant, 2014-2015); Current Position: Ph.D. student at IISER-M, India
  • Arsila Ashraf (BS-MS student IISER-Mohali, Batch: 2011-15)
  • Partha Sankar (BS-MS student IISER-Mohali, Batch: 2011-15), currently PhD student at NCBS, Bangalore, India
  • Vivek B. Raina (BS-MS student, IISER-Mohali, Batch: 2010-14), currently PhD student at the International Max-Planck-Research School in Chemical and Molecular Biology
  • Irfana Saleem (BS-MS student, IISER-Mohali, Batch: 2010-14), currently PhD student at University of Nebraska Medical Center
  • Neelam Singh (BS-MS student, IISER-Mohali, Batch 2009-13)
  • Surbhi Bahl (Post-doctoral fellow)