Michael S. Marks, Ph.D.

faculty photo
Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine

Contact information
Children's Hospital of Philadelphia Research Institute
1107B Abramson Research Center
3615 Civic Center Blvd.
Philadelphia, PA 19104
Office: (215) 590-3664
Lab: (215) 590-3944
Education:
B.S. (Biological Sciences)
Cornell University, 1982.
Ph.D. (Immunology/Microbiology)
Duke University Durham, NC, 1989.
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Description of Research Expertise

Research Interests
Regulation and diseases of intracellular protein transport and organelle biogenesis.
Regulation of the formation of functional amyloid in organelle biogenesis.
Regulation of antigen processing and toll-like receptor signaling by endosomal trafficking pathways.

Key words: Melanosome, lysosome, melanoma, intracellular protein transport, vesicles, secretory lysosomes, Hermansky Pudlak syndrome, amyloid, protein sorting, platelets, antigen processing, major histocompatibility complex molecules, toll-like receptors.

Description of Research
The central vacuolar system of eukaryotic cells is compartmentalized into distinct membrane-bound organelles and vesicular structures, each with its own characteristic function and set of protein constituents. Work in my laboratory is focused on understanding how integral membrane protein complexes are assembled and sorted to the appropriate compartments within the late secretory and endocytic pathways, and how sorting and assembly contribute to the biogenesis of specific organelles in several cell types and to immune regulation.

Our primary focus over the past 10 years has been on melanosomes of pigmented cells. Melanosomes are unique lysosome-related organelles present only in cells that make melanin, the major synthesized pigment in mammals. Melanosomes are among a number of tissue-specific lysosome-related organelles that are malformed and dysfunctional in a group of rare heritable disorders, including Hermansky-Pudlak and Chediak-Higashi syndromes, and pigment cell-specific proteins that localize to melanosomes are targets for the immune system in patients with melanoma. In an effort to understand the molecular basis of these diseases, we are dissecting the molecular mechanisms that regulate how different stage melanosomes are formed and integrated with the endosomal pathway. We use biochemical, morphological, and genetic approaches to follow the fates of melanosome-specific and ubiquitous endosomal and lysosomal proteins within pigment cells from normal individuals or mice and disease models. Using these approaches, we are (1) outlining protein transport pathways that lead to the formation of these unusual organelles, (2) dissecting biochemical pathways that lead to their morphogenesis, and (3) defining how these processes are subverted by genetic disease. Current efforts focus on how factors that are deficient in patients and mouse models of the genetic diseease, Hermansky-Pudlak syndrome, impact melanosome biogenesis. These factors interact with classical components of the membrane trafficking machinery such as SNAREs and coats, and we are dissecting how these interactions result in the delivery of cargoes to unique organelle structures in these cells. We are particularly interested in the formation of tubular connections between endosomes and maturing melanosomes, as several factors that are disrupted in Hermansky-Pudlak syndrome impact the formation and/or dynamics of these transport carriers.

Because genetic diseases like Hermansky-Pudlak syndrome affect multiple organ systems, we have initiated two new projects to dissect how similar sorting processes involved in melanosome biogenesis influence other organelles in different cell types. The first involves lysosome-related organelles in platelets called dense granules and alpha granules. Dense granules are organelles within platelets that store small molecules such as adenine nucleotides, polyphosphate, serotonin and calcium that are released upon platelet activation and are required for optimal blood clotting. Like melanosomes, dense granules are malformed in Hermansky-Pudlak syndrome, and we are studying how dense granule contents are delivered within platelets and their precursors (megakaryocytes). In collaboration with Mitch Weiss and Morty Poncz at CHOP, we are studying how cargoes of dense granules are delivered to those organelles in megakaryocytes, and how these processes are altered in Hermansky-Pudlak syndrome and other bleeding disorders. Alpha granules are other lysosome-related organelles in platelets that store secretory protein contents. In collaboration with Morty Poncz and Gerd Blobel, we are studying how alpha granule secretion is altered in a mouse model of a human bleeding disorder.

The second cellular system is the dendritic cell, a master regulator of T cell immune function. Dendritic cells have been proposed to harbor a lysosome-related organelle involved in preventing maturation of phagosomes to facilitate the processing of phagocytosed antigens to stimulate CD8+ (prdominantly cytotoxic) T cells. Paradoxically, we have found that dendritic cells from one Hermansky-Pudlak syndrome model are impaired in their ability to process phagocytosed antigen for presentation to a different class of T cells, the CD4+ (predominantly T helper) T cells. Preliminary studies suggest that the antigen processing defect results from a primary defect in toll-like receptor signalling from phagosomes, and current projects are devoted to better understanding this defect at the molecular level.

Melanosome precursors harbor intralumenal fibrils upon which melanins deposit in later stages. The main component of these fibrils is a pigment cell-specific protein, Pmel17. Fibrils formed by Pmel17 in vitro display features common with amyloid formed in disease states such as Alzheimer's disease and the prion diseases. We hope that by dissecting how Pmel17 forms amyloid like fibrils under physiological conditions, we may not only understand melanosome biogenesis but also the formation of amyloid under pathological conditions.



Rotation Projects for 2013-2014
1. Define metal import defects in melanocytes from mouse models of Hermansky-Pudlak syndrome types 7-9.
2. Assess role of Sec1/Munc18 family members in regulating melanosome biogenesis.
3. Dissect functional interactions between BLOC-1 or BLOC-2 and SNARE proteins during organelle biogenesis.
4. Define targeting signals for incorporation of transmembrane cargo proteins in megakaryocyte dense granules or lung epithelial cell lamellar bodies.
5. Assess phosphoinositide distribution during phagosome maturation in dendritic cells.
6. Test for anterograde and retrograde trafficking defects in dendritic cells and macrophages from Hermansky-Pudlak syndrome model mice.

Lab personnel:
Adriana Mantegazza - Senior Scientist
Megan Dennis - Post-doctoral researcher
Ariel Lefkovith – BGS Graduate Student (CAMB)
Tina Ho – BGS Graduate Student (CAMB)
Dawn Harper - Research Associate
Amanda Acosta - Undergraduate researcher
Alexis Borden - Undergraduate researcher

Selected Publications

Mantegazza AR, Zajac AL, Twelvetrees A, Holzbaur EL, Amigorena S and Marks MS: TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation. Proc. Natl. Acad. Sci. U.S.A. In press, 2014.

Min SH, Suzuki A, Stalker TJ, Zhao L, Wang Y, McKennan C, Riese MJ, Guzman JF, Zhang S, Lian L, Joshi R, Meng R, Seeholzer SH, Choi JK, Koretzky G, Marks MS and Abrams CS: Loss of PIKfyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice. Nat. Commun. 5: 4691, September 2014.

Delevoye C, Miserey-Lenkei S, Montagnac G, Gilles-Marsens F, Paul-Gilloteaux P, Giordano F, Waharte F, Marks MS, Goud B and Raposo G: Recycling endosome tubule morphogenesis from sorting endosomes requires the kinesin motor KIF13A. Cell Rep. 6(3): 445-454, February 2014.

Marks MS, Heijnen HFG and Raposo G: Lysosome-related organelles: Unusual compartments become mainstream. Curr. Opin. Cell Biol. 25(4): 495-505, August 2013.

Watt B, van Niel G, Raposo G and Marks MS: PMEL: A pigment cell-specific model for functional amyloid formation. Pigment Cell and Melanoma Res. 26(3): 300-315, May 2013.

*Theos AC, *Watt B, Harper DC, Janczura KJ, Theos SC, Herman KE and Marks MS: The PKD domain distinguishes the trafficking and amyloidogenic properties of the pigment cell protein PMEL and its homologue GPNMB. Pigment Cell Melanoma Res. 26(4): 470-486, July 2013.

Sitaram A, Dennis MK, Chaudhuri R, De Jesus-Rojas W, Tenza D, Setty SRG, Wood CS, Sviderskaya EV, Bennett DC, Raposo G, Bonifacino JS and Marks MS: Differential recognition of a dileucine-based sorting signal by AP-1 and AP-3 reveals a requirement for both BLOC-1 and AP-3 in delivery of OCA2 to melanosomes. Mol. Biol. Cell 23(16): 3178-3192, August 2012.

Meng R, Wang Y, Yao Y, Zhang Z, Harper DC, Heijnen HFG, Sitaram A, Li W, Raposo G, Weiss MJ, Poncz M and Marks MS: SLC35D3 delivery from megakaryocyte early endosomes is required for platelet dense granule biogenesis and differentially defective in Hermansky-Pudlak syndrome models. Blood 120(2): 404-414, July 2012.

Mantegazza AR, Guttentag SH, El-Benna J, Sasai M, Iwasaki A, Shen H, Laufer TM and Marks MS: Adaptor protein-3 in dendritic cells facilitates phagosomal Toll-like receptor signaling and antigen presentation to CD4+ T cells. Immunity 36(5): 782-794, May 2012.

Sitaram A and Marks MS: Mechanisms of protein delivery to melanosomes in pigment cells. Physiology 27(2): 85-99, April 2012.

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Last updated: 09/27/2014
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