PEOPLE

Michael S. Marks, PhD

Professor of Pathology and Laboratory Medicine
Professor of Physiology
University of Pennsylvania Perelman School of Medicine

Contact InformationChildren's Hospital of Philadelphia Research Institute
816G Abramson Research Center
3615 Civic Center Blvd.
Philadelphia, PA 19104
Office: (215) 590-3664

Email: marksm@pennmedicine.upenn.edu

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.
Melanosome maturation.
Biology of platelet granules.

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

Description of Research
Eukaryotic cells are 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, how sorting and assembly contribute to the biogenesis of cell type-specific organelles, how these processes impact biological function in the pigmentary, blood clotting, and immune systems, and how they are thwarted by generally rare genetic diseases.

Our primary focus over the past 20 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. Genetic defects in melanosome constituents or in their delivery to nascent melanosomes result in ocular or oculocutaneous albinism, characterized by lack of pigmentation in the eyes and or skin and concomitant visual impairment and susceptibility to skin and ocular cancers. 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. 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 the molecular mechanisms by which factors that are deficient in patients and mouse models of the genetic disease, Hermansky-Pudlak syndrome, impact melanosome biogenesis. We are particularly interested in how these factors contribute to the formation and dynamics of tubular connections between endosomes and maturing melanosomes that facilitate cargo transport, as well as the formation of retrograde membrane carriers that retrieve unneeded proteins from melanosomes.

In addition to these studies, we are interested in the function of individual melanosome and lysosome components and how they impact melanogenesis. For example, melanosome precursors in pigment cells harbor internal fibrils upon which melanins deposit in later stages, the main component of which is a pigment cell-specific protein, PMEL. Fibrils formed by PMEL in vitro display features common with amyloid formed in disease states such as Alzheimer and Parkinson diseases. By dissecting how PMEL forms amyloid under physiological conditions, we hope to determine how the formation of "good" and "bad" amyloid differs and thus how the formation of "bad" amyloid might be controlled. Other melanosomal proteins are transporters that impact the intralumenal environment of melanosomes to alter the type and amount of melanin that is made. Together with our collaborators we are studying the biophysical function of these transporters and how they are linked to features such as melanosome pH.

Because genetic diseases like Hermansky-Pudlak syndrome affect multiple organ systems, we study 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. When platelets are activated at sites of blood vessel damage, the contents of these granules are released, leading to optimal blood clot formation and platelet activation. Like melanosomes, dense granules are malformed in Hermansky-Pudlak syndrome, and in collaboration with the Poncz, Stalker and French laboratories at CHOP and Penn we are studying how dense granule contents are delivered within platelets and their precursors (megakaryocytes). Studies in collaboration with the Poncz and French labs also address the contents and secretion of alpha granules and their disruption in human bleeding disorders.

The second cellular system is the dendritic cell, a master regulator of T cell-mediated immunity. Patients with Hermansky-Pudlak syndrome type 2 have recurrent bacterial infections, and we have found that this is at least in part due to defects in the way that dendritic cells sense bacterial infection. Normally, ingested bacteria trigger signaling by innate immune receptors present on the membrane enclosing the bacteria (the phagosome) or in the cytoplasm; signaling by both sets of receptors is defective in dendritic cells from a mouse model of the disease due to (1) impaired recruitment of the receptors and their signaling platforms on phagosomes and (2) rapid clearing of cytoplasmic receptors by autophagy. Ongoing studies aim to dissect how phagosome membrane dynamics normally lead to signaling and how this is altered in disease states.





Rotation Projects for 2018-2019
1. Test how lysosomal pH impacts melanogenesis and the consequences of lysosome: melanosome interactions in cells.
2. Assess the role of BLOC-2 (defective in some Hermansky-Pudlak syndrome variants) in stabilizing membrane tubules on microtubules.
3. Dissect the localization of regulators of MC1R signaling in melanocytes and how they impact MC1R localizaton.
4. Assist in establishing a cell line model for monocyte inflammasome hyperactivation in Hermansky-Pudlak syndrome models.
5. Assist in purification of dense granules from platelets for proteomic studies.


Lab personnel:
Adriana Mantegazza - Senior Scientist
Shanna Bowman - Post-doctoral fellow
Jing Bi Karchin - Post-doctoral fellow
Linh Le - BGS Graduate Student (CAMB)
Yueyao Zhu - Biology Graduate Student
Dawn Harper - Research Associate
Preethi Kumaran - Undergraduate Researcher

Graduate Groups

Biochemistry and Molecular Biophysics
Cell and Molecular Biology
Immunology
Pharmacology

Education

B.S. (Biological Sciences), Cornell University, 1982
Ph.D. (Immunology/Microbiology), Duke University Durham, NC, 1989

Specialty Certification

Postgraduate Training

IRTA Fellow (1989-1990) and Staff Fellow (1990-1992), Laboratory of Developmental and Molecular Immunity and Laboratory of Molecular Growth Regulation, NICHD, NIH, Bethesda, MD. Mentor: Dr. Keiko Ozato, 1989-1992
NRSA Fellow (1992-1993) and IRTA Fellow (1993-1995), Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD. Mentor: Dr. Juan Bonifacino, 1992-1995

Awards and Honors

National Science Foundation pre-doctoral fellowship, 1983-1986
Duke Univ. merit scholarship, 1983-1987
NRSA post-doctoral fellowship, 1992-1993
NIH Fellows Award for Research Excellence, 1995-1995
Aaron B. Lerner Lectureship/ Pan-American Society for Pigment Cell Research, 2009
Fellow, American Association for the Advancement of Science, 2016

Memberships and Professional Organizations

American Assoc. of Immunologists, 1990 - Present
American Society for Cell Biology, 1994 - Present
American Assoc. for the Advancement of Science, 1994 - Present
Earth and Life Sciences Council, MEERVOUD program, The Netherlands, 2003 - 2003
National Science Foundation, 2003 - 2003
ZAR1 AAA-G J1 Scientific Review Group, NIAMS, National Insitutes of Health, 2003 - 2003
The Netherlands Organisation for Health Research and Development (ZonMw), 2003 - 2003
Whitehead Fellowships for Junior Faculty in Biomedical or Biological Sciences, New York University, 2003 - 2003
Dutch Cancer Society, The Netherlands, 2004 - 2004
R21 High Risk RFA Scientific Review Group, NIAMS, National Institutes of Health, 2004 - 2004
Swiss National Science Foundation, 2004 - 2004
AMS 2007-01 Scientific Review Group, NIAMS, National Institutes of Health, 2006 - 2006
ZAR1 EHB-D M1 (Small Research Grants) Scientific Review Group, NIAMS, National Institutes of Health, 2008 - 2008
American Society for Biochemistry and Molecular Biology, 2008 - 2012
Pan-American Society for Pigment Cell Research, 2008 - 2012
Medical Research Council, UK, 2009 - 2009
Board of Scientific Counselors Review and Evaluation of Intramural Programs, NIDCR, National Institutes of Health, 2010 - 2010
ACTS Scientific Review Group, National Institutes of Health, 2011 - 2011
ZRG1 MDCN B91 Scientific Review Group, National Institutes of Health, 2012 - 2012
British Biomedical Science Research Council, 2013 - 2013
ACTS Scientific Review Group, National Institutes of Health, 2013 - 2015
Board of Scientific Counselors Review and Evaluation of Intramural Programs, NIDCR, National Institutes of Health, 2013 - 2013
Netherlands Organisation for Scientific Research (NWO), 2013 - 2013
European Society for Pigment Cell Research, 2013 - present
Medical Research Council, UK, 2015 - 2015
Membrane Biology and Protein Processing Study Section, NIH, 2015 - 2017
4th European Days of Albinism, 2017 - present
MBPP (membrane biology and protein processing) study section member, 2017 - 2021

Web Links


Selected Publications

Myosin VI and actin dynamics induce membrane constriction and fission for recycling from melanosomes

Ripoll L, Heiligenstein X, Hurbain I, Domingues L, Figon F, Petersen KJ, Dennis MK, Houdusse A, Marks MS, Raposo G and Delevoye C, J. Cell Biol. 217(8): 2709-2726, 2018, PMID:29875258

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Novel loci associated with skin pigmentation identified in African populations

Crawford NG, Kelly DE, Hansen MEB, Beltrame MH, Fan S, Bowman SL, Jewett E, Ranciaro A, Thompson S, Lo Y, Pfeifer SP, Jensen JD, Campbell MC, Beggs W, Hormozdiari F, Mpoloka SW, Mokone GG, Nyambo T, Meskel DW, Belay G, Haut J, NISC Comparative Sequencing Program, Rothschild H, Zon L, Zhou Y, Kovacs MA, Xu M, Zhang T, Bishop K, Sinclair J, Rivas C, Elliot E, Choi J, Li SA, Hicks B, Burgess S, Abnet C, Watkins-Chow DE, Oceana E, Song YS, Eskin E, Brown KM, Marks MS, Loftus SK, Pavan WJ, Yeager M, Chanock S and Tishkoff S, Science 358(6365): eaan8433, 2017, PMID:29025994

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Platelet dense granules begin to selectively accumulate mepacrine during proplatelet formation

Hanby HA, Bao J, Noh J-Y, Jarocha D, Poncz M, Weiss MJ and Marks MS, Blood Advances 1(19): 1478-1490, 2017, PMID:28936487

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BLOC-1 and BLOC-3 regulate VAMP7 cycling to and from melanosomes via distinct tubular transport carriers

Dennis MK, Delevoye C, Acosta-Ruiz A, Hurbain I, Romao M, Hesketh GG, Goff PS, Sviderskaya EV,Bennett DC, Luzio JP, Galli T, Owen DJ, Raposo G, Marks MS, J. Cell Biol. 214(3): 293-308, 2016, PMID:27482051

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BLOC-1 brings together the actin and microtubule cytoskeletons to generate recycling endosomes

Delevoye C, Heiligenstein X, Ripoll L, Gilles-Marsens F, Dennis MK, Linares RA, Derman L, Gokhale A, Morel E, Faundez V, Marks MS and Raposo G, Curr. Biol. 26(1): 1-13, 2016, PMID:26725201

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BLOC-2 targets recycling endosomal tubules to melanosomes for cargo delivery

*Dennis MK, *Mantegazza AR, Snir OL, Tenza D, Acosta-Ruiz A, Delevoye C, Zorger R, Sitaram A, de Jesus-Rojas W, Ravichandran K, Rux J, Sviderskaya EV, Bennett DC, Raposo G, Marks MS** and **Setty SRG, J. Cell Biol. 209(4): 563-577, 2015, PMID:26008744

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Defective release of alpha-granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models

Meng R, Wu J, Harper DC, Wang Y, Kowalska MA, Abrams CS, Brass LF, Poncz M, Stalker TJ, and Marks MS, Blood 125(10): 1623-1632, 2015, PMID:25477496

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An intracellular anion channel critical for pigmentation

Bellono N, Escobar IE, Lefkovith AJ, Marks MS and Oancea EV, eLife 3(): e04543, 2014, PMID:25513726

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TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation

Mantegazza AR, Zajac AL, Twelvetrees A, Holzbaur EL, Amigorena S and Marks MS, Proc. Natl. Acad. Sci. U.S.A. 111(43): 15508-15513, 2014, PMID:25313083

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