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
816G Abramson Research Center
3615 Civic Center Blvd.
Philadelphia, PA 19104
Office: (215) 590-3664
Lab: (215) 590-3944
B.S. (Biological Sciences)
Cornell University, 1982.
Ph.D. (Immunology/Microbiology)
Duke University Durham, NC, 1989.
Cert (iCARE Training on Crisis Management)
CAPS, Perelman School of Medicine, 2019.
Cert. (Unconscious Bias for Leaders - Impact on Decision-Making)
Perelman School of Medicine, 2020.
Cert. (Research Mentor Training: Effective Communication and Aligning Expectations)
Perelman School of Medicine, 2022.
Cert. (Unconscious Bias for Leaders)
CHOP, 2023.
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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.
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 25 years has been on melanosomes of pigmented cells. Melanosomes are unique lysosome-related organelles present only in cells that make melanin, the major skin and eye pigment synthesized by 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, live cell imaging, 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 the molecular control of 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. Additional proteins of interest come from genetic screens by our collaborators such as Sarah Tishkoff at Penn, who has identified many genes that impact skin pigmentation in human populations.

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 non-pigment 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 2023-2024
1. Test how lysosomal pH impacts melanogenesis and the consequences of lysosome: melanosome interactions in cells.
2. Test whether vATPase distribution plays a role in deacidification of maturing melanosomes.
3. Assess lysosomal and/or melanosomal damage in cells expressing hypopigmentation-associated PMEL variants.
4. Localize the products of new pigmentation genes in melanocytes.
5. Assist in establishing a cell line model for monocyte inflammasome hyperactivation in Hermansky-Pudlak syndrome models.
6. Define the basis for heterogeneity of late endosomal/ lysosomal compartments in megakaryocytes.

Lab personnel:
Dawn Harper - Research Associate
Roseanne Davila-Rivera - Graduate Student (BMB)
Santanu Das - Post-doctoral fellow
Rachel Tocci - Research Technician
Brice Magne - Post-doctoral fellow (starting 5/2023)
Matias Schmukler - Undergraduate researcher
Corina Nava - Undergraduate researcher

Selected Publications

Puckett EE, Davis IS, Harper DC, Wakamatsu K, Battu G, Belant JL, Beyer D, Carpenter C, Crupi A, Davidson M, DePerno C, Forman N, Fowler NL, Garshelis DL, Gould N, Gunther K, Haroldson M, Ito S, Lackey C, Leahy R, Lee-Roney C, Lewis T, Lutto A, McGowan K, Olfenbuttel C, Orlando M, Platt A, Pollard M, Ramaker M, Reich H, Sell SK, Strules J, van Manen F, Whiman C, Williamson R, Winslow F, Kaelin C, Marks MS and Barsh G: Genetic architecture and evolution of color variation in North American black and brown bears. Curr. Biol. 33(1): 1-12, January 2023 Notes: doi: 10.1016/j.cub.2022.11.042.

Zhu Y, Li S, Jaume A, Jani RA, Delevoye C, Raposo G and Marks MS: Type II phosphatidylinositol 4-kinases function sequentially in cargo delivery from early endosomes to melanosomes. J. Cell Biol. 221(11): e202110114, November 2022.

Kook S, Wang P, Meng S, Jetter CS, Gokey J, Sucre JMS, Benjamin J, Gokey J, Hanby HA, Jaume A, Goetzl L, Marks MS and Guttentag SH: AP-3-dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells. Proc. Natl. Acad. Sci. U.S.A. 118(20): e2025208118, May 2021.

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: A BLOC-1-AP-3 super-complex sorts a cis-SNARE complex into endosome-derived tubular transport carriers. J. Cell Biol. 220(7): e202005173, July 2021.

Le L, Sires-Campos J, Raposo G, Delevoye C and Marks MS.: Melanosome biogenesis in the pigmentation of human skin. Integr. Comp. Biol. 61(4): 1517-1545, October 2021.

Lopez-Haber C, Levin-Konigsberg R, Zhu Y, Bi-Karchin J, Ball T, Grinstein S, Marks MS, and Mantegazza AR: Phosphatidylinositol-4-kinase IIalpha licences phagosomes for TLR4 signaling and MHC-II presentation in dendritic cells. Proc. Natl. Acad. Sci. U.S.A. 117(45): 28251-28262, November 2020.

Le L, *Escobar IE, *Ho T, *Lefkovith AJ, Latteri E, Haltaufderhyde KD, Dennis MK, Plowright L, Sviderskaya EV, Bennett DC, **Oancea E, **Marks MS: SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation. Mol. Biol. Cell 31(24): 2687-2702, November 2020 Notes: * - authors contributed equally ** - authors contributed equally.

Pennamen P, Le L, Tingaud-Sequeira A, Fiore M, Bauters A, Van Duong BĂ©atrice N, Coste V, Bordet J-C, Plaisant C, Diallo M, Michaud V, Trimouille A, Lacombe D, Lasseaux E, Delevoye C, Picard FM, Delobel B, Marks MS and Arveiler B: BLOC1S5 pathogenic variants cause a new type of Hermansky-Pudlak Syndrome. Genet.Med. 22(10): 1613-1622, October 2020.

*Bowman SL, *Karchin JB, *Le L and Marks MS: The road to LROs: insights into lysosome-related organelles from Hermansky-Pudlak syndrome and other rare diseases. Traffic 20(6): 404-435, June 2019.

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: Novel loci associated with skin pigmentation identified in African populations. Science 358(6365): eaan8433, November 2017.

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Last updated: 03/07/2024
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