Michael S. Marks, Ph.D.
816G Abramson Research Center
3615 Civic Center Blvd.
Philadelphia, PA 19104
Lab: (215) 590-3944
B.S. (Biological Sciences)
Cornell University, 1982.
Duke University Durham, NC, 1989.
Description of Research ExpertiseResearch 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.
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.
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
Selected PublicationsRipoll L, Heiligenstein X, Hurbain I, Domingues L, Figon F, Petersen KJ, Dennis MK, Houdusse A, Marks MS, Raposo G and Delevoye C: Myosin VI and actin dynamics induce membrane constriction and fission for recycling from melanosomes. J. Cell Biol. 217(8): 2709-2726, August 2018.
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.
Hanby HA, Bao J, Noh J-Y, Jarocha D, Poncz M, Weiss MJ and Marks MS: Platelet dense granules begin to selectively accumulate mepacrine during proplatelet formation. Blood Advances 1(19): 1478-1490, August 2017.
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: BLOC-1 and BLOC-3 regulate VAMP7 cycling to and from melanosomes via distinct tubular transport carriers. J. Cell Biol. 214(3): 293-308, August 2016 Notes: doi: 10.1083/jcb.201605090.
Ho T, Watt B, Spruce LA, Seeholzer SH and Marks MS: The Kringle-Like Domain facilitates post-endoplasmic reticulum changes to PMEL oligomerization and disulfide bond configuration and promotes amyloid formation. J. Biol. Chem. 291(7): 3595-3612, February 2016.
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: BLOC-1 brings together the actin and microtubule cytoskeletons to generate recycling endosomes. Curr. Biol. 26(1): 1-13, January 2016.
*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: BLOC-2 targets recycling endosomal tubules to melanosomes for cargo delivery. J. Cell Biol. 209(4): 563-577, May 2015 Notes: *, ** Equal contributions. Marks MS is corresponding author.
Meng R, Wu J, Harper DC, Wang Y, Kowalska MA, Abrams CS, Brass LF, Poncz M, Stalker TJ, and Marks MS: Defective release of alpha-granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models. Blood 125(10): 1623-1632, March 2015.
Bellono N, Escobar IE, Lefkovith AJ, Marks MS and Oancea EV: An intracellular anion channel critical for pigmentation. eLife 3: e04543, December 2014.
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. 111(43): 15508-15513, October 2014.