Field of Biochemistry, Molecular and Cell Biology

Ph.D. Thesis Defense Seminar

Mariela Núñez Santos

Hu Lab

Monday, October 17, 2022, 10:00 AM

G01 Biotechnology Building

Zoom Meeting Link:

https://cornell.zoom.us/j/99634705132?pwd=RHc0bXNLRWF2d2RDZ1JCalZROEFkQT09

Meeting ID: 996 3470 5132

Passcode: 689674s

“Interactions Between Progranulin, CD68, and Gas6 and Implications for Inflammation and Neurodegeneration”

Frontotemporal Lobar degeneration (FTLD) is the second most common form of early onset dementia characterized by the progressive atrophy of frontal and temporal lobes, resulting in behavior, cognitive, and language dysfunction. Mutations in the GRN gene, encoding the progranulin (PGRN) protein, have been identified as a causative genetic basis for FTLD. PGRN is a secreted glycoprotein involved in an array of cellular processes including tumorigenesis, wound healing, lysosomal function, and inflammatory responses. PGRN can be cleaved into 7.5 granulin peptides (GRN A, B, C, D, E, F, G, and the paragranulin fragment) which can have independent functions. PGRN functions both in the lysosome by regulating the activities of multiple lysosomal proteins and extracellularly by interacting with another set of proteins to regulate cell survival and signaling. In the brain, PGRN is essential for proper microglia-mediated activities. In this work, we show that the two pools of PGRN, intracellular and extracellular, have unique binding partners necessary for regulating inflammatory processes. Intracellularly, PGRN-derived granulin E binds to CD68, a lysosomal membrane protein involved in microglia activation, and together they reciprocally regulate their protein homeostasis. I provide evidence that CD68 is required for the stability of the GRN E peptide while PGRN is required to prevent alterations in CD68 molecular weight. Furthermore, I show that the extracellular pool of PGRN binds to Gas6, a secreted glycoprotein involved in phagocytosis and inflammation, and regulates Gas6 levels.  Altogether, my data reveals novel mechanisms by which PGRN regulates inflammatory responses.

 Publications:

1. Mariela Nunez Santos, Daniel H. Paushter, Tingting Zhang, Xiaochun Wu, Huan Du, Nicolas Mui, Jiaoying Lou, and Fenghua Hu. Progranulin-derived granulin E and lysosome membrane protein CD68 interact reciprocally to regulate their protein homeostasis.Journal of Biological Chemistry. 2022. 298(9): p. 102348.
2. Mariela Nunez Santos, Tingting Zhang, Matteui Zhai, and Fenghua Hu. Progranulin Interacts with Gas6 to regulate its expression and trafficking.  In preparation.
3. Tingting Zhang, Huan Du, Mariela Nunez Santos, Xiaochun Wu, Thomas Reinheckel and Fenghua Hu. Differential regulation of progranulin-derived granulin peptides. Molecular Neurodegeneration. 2022. 15(17).
4. Tingting Zhang¹, Jennifer Guo, Kenton Wu, Mariela Nunez Santos¹, Alissa Nana², William W. Seeley², Fenghua Hu. TMEM106B regulates microglial proliferation and survival in response to demyelination. Science Advances. Accepted.
5. Huan Du¹, Tingting Zhang¹, Mariela Nunez Santos¹, Charlene Hsu¹, Junke Zhang², Haiyuan Yu², and Fenghua Hu¹. Lysosome Abnormalities caused by progranulin deficiency lead to enhanced inflammatory response to Amyloid-beta plaques. Life Science Alliance. 2021. 136(1): 1–17
6. Xiaolai Zhou¹, Daniel H. Paushter¹, Mitchell D Pagan¹, Dongsung Kim¹, Mariela Nunez Santos¹, Raquel L Lieberman², Herman S Overkleeft³, Ying Sun⁴, Marcus B Smolka¹, and Fenghua Hu¹. Progranulin Deficiency leads to reduced glucocerebrosidase activity. PLoS One. 2019 Jul 10;14(7):e0212382.