Michael S. Marks

Professor

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215-590-3664
marksm@pennmedicine.upenn.edu

816G Abramson Research Center

3615 Civic Center Blvd.

Philadelphia, PA 19104

Research Description

The central vacuolar system of eukaryotic cells is compartmentalized into distinct membrane-bound organelles and tubulovesicular 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 several cell type-specific organelles and to the regulation of immunity and hemostasis.

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. Melanosomes are among a number of tissue-specific lysosome-related organelles (LROs) that are malformed and dysfunctional in a group of rare heritable disorders, including Hermansky-Pudlak and Chediak-Higashi syndromes. Moreover, mutations in genes encoding pigment cell-specific proteins underlie various forms of non-syndromic oculocutaneous and ocular albinism. 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, and how specific non-enzymatic melanosome components contribute to melanin synthesis.  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) detailing protein transport pathways that lead to the formation of these unusual organelles, (2) dissecting biochemical pathways that lead to their morphogenesis, (3) defining how these processes are subverted by genetic disease, and (4) understanding how genetic variation impacts skin pigmentation. Current efforts focus on how factors that are deficient in patients and mouse models of 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. We are also focused on how a number of genes impact pigmentation by altering the lumenal pH of melanosomes or of lysosomes that interact transiently with melanosomes inside melanocytes.

Because genetic diseases like Hermansky-Pudlak syndrome affect multiple organ systems, we are dissecting how similar sorting processes involved in melanosome biogenesis influence other organelles in different cell types. The first involves LROs in platelets called dense granules and alpha granules. Dense granules store 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. In collaboration with a variety of investigators at CHOP and Penn Medicine, we are studying how dense granule contents are delivered within platelets and their precursors (megakaryocytes) and how these processes are altered in Hermansky-Pudlak syndrome and other bleeding disorders. Additional collaborative studies focus on the formation and protein targeting to alpha granules, which are distinct LROs in platelets that store secretory protein contents. In collaboration with Susan Guttentag at Vanderbilt, we are extending our knowledge of melanosome biogenesis to the lamellar bodies of alveolar type 2 cells in the lung. These LROs synthesize and store surfactant, and are also disrupted in several forms of Hermansky-Pudlak syndrome. We are identifying lamellar body components and the pathways by which they access nascent lamellar bodies. A third cellular system is the dendritic cell, a master regulator of T cell immune function. We have found that in dendritic cells from a mouse model of Hermansky-Pudlak syndrome type 2, phagocytosed particles elicit impaired signaling to activate innate immune functions, with consequent impairment in activating CD4+ T cells of the adaptive immune system against particulate invaders such as bacteria. We are trying to understand the molecular bases of these effects and their link to antigen presentation.

Finally, melanosome precursors harbor intralumenal fibrils upon which melanins deposit in later stages. The main component of these fibrils is a pigment cell-specific protein, PMEL. Fibrils formed by PMEL in vitro resemble amyloid formed in neurodegenerative diseases such as Alzheimer, Parkinson, and prion diseases. We hope that by dissecting how PMEL forms amyloid under physiological conditions, we may not only understand melanosome biogenesis but also the formation of amyloid under pathological conditions.

Diversity & Inclusion Initiatives

  • Trainer, PennPORT program (two post-doctoral fellows, 2010-2018)
  • Trainer, Summer Undergraduate Internship Program (1997-2020)
  • Trainer, HHMI summer undergraduate program (1998)
  • Trainer, Univ. of Pennsylvania diversity undergraduates (1996-2020)
  • ACT Discussion leader
Degrees & Education

BS, (Biological Sciences) Cornell University, 1982

PhD, (Immunology/Microbiology) Duke University Durham, NC, 1989

Honors & Awards

1983 - 1986 National Science Foundation pre-doctoral fellowship

1983 - 1987 Duke University merit scholarship

1992 - 1993 NRSA post-doctoral fellowship

1995 NIH Fellows Award for Research Excellence

2009 Aaron B. Lerner Lectureship, Pan-American Society for Pigment Cell Research

2016 Fellow of the American Association for the Advancement of Science (AAAS)

2019 Award for Excellence in Mentoring Research Trainees, Children's Hospital of Philadelphia

Other Perelman School of Medicine Affiliations

Dept. of Pathology and Laboratory Medicine

Children’s Hospital of Philadelphia Research Institute

Professional Affiliations

1990 - 1992, 1996-present, Member, American Association of Immunologists

1994 - present, Member, American Society for Cell Biology

1994 - present, Member, American Assoc. for the Advancement of Science

2000 - 2005, Associate Editor, Journal of Immunology

2004 - present, Editorial board, Pigment Cell and Melanoma Research

2004 - 2008, Editorial board, Traffic

2006 - 2020, Board of Reviewing Editors, Molecular Biology of the Cell

2008 - 2011, Associate Editor, Traffic

2008 – present, Member, American Society for Biochemistry and Molecular Biology

2008 – present, Member, Pan-American (2008-2013) or European (since 2013) Society for Pigment Cell Research

2010 – 2012, Council, Pan-American Society for Pigment Cell Research

2011 - 2015, Editorial board, Journal of Cell Science

2012, Chair, Gordon Research Conference on Lysosomes and Endocytosis

2012 - 2020, Co-editor, Traffic

2013 - present, Guest editor, PLoS Genetics

2013 – 2017, Ad hoc member, ACTS and MBPP study sections, National Institutes of Health

2014, Local Organizer, American Society for Cell Biology Annual Meeting

2017 - present, Scientific Committee, European Days of Albinism

2017 - 2021, Member, MBPP study section, National Institutes of Health

2019 - 2021, Chair, MBPP study section, National Institutes of Health

2021 - present, Editor, Molecular Biology of the Cell

Recent Publications
October 14, 2021
Melanosome Biogenesis in the Pigmentation of Mammalian Skin
Michael S. Marks, Ph.D.
Le L, Sirés-Campos J, Raposo G, Delevoye C, Marks MS - doi: 10.1093/icb/icab078
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October 14, 2021
Melanin Transfer and Fate within Keratinocytes in Human Skin Pigmentation
Michael S. Marks, Ph.D.
Benito-Martínez S, Salavessa L, Raposo G, Marks MS, Delevoye C. - doi: 10.1093/icb/icab094
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May 18, 2021
AP-3-dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells
Michael S. Marks, Ph.D.
Kook S, Wang P, Meng S, Jetter CS, Sucre JMS, Benjamin JT, Gokey JJ, Hanby HA, Jaume A, Goetzl L, Marks MS, Guttentag SH - doi: 10.1073/pnas.2025208118
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April 22, 2021
A BLOC-1:AP-3 super-complex sorts a cis-SNARE complex into endosome-derived tubular transport carriers
Michael S. Marks, Ph.D.
Bowman SL, Le L, Zhu Y, Harper DC, Sitaram A, Theos AC, Sviderskaya EV, Bennett DC, Raposo G, Owen DJ, Dennis MK and Marks MS - DOI: 10.1083/jcb.202005173
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March 22, 2021
How a membrane transporter keeps melanocytes in the red
Michael S. Marks, Ph.D.
Marks MS and Pavan WJ - DOI: 10.1111/pcmr.12973
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December 21, 2020
A new direction for Traffic
Michael S. Marks, Ph.D.
Marks MS, Parton RG, Schroer TA, Tooze SA, Brodsky FM, Marsh M, Schmid SL, Griffiths GM, Stevens TH and van Meer G - DOI: 10.1111/tra.12763
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