Yihong Ye, Ph.D.
Protein Stability and Quality Control Section, Laboratory of Molecular Biology
Building 5, Room 433
5 Memorial Dr
Bethesda, MD 20814
+1 301 594 0845
The ultimate goal of our research is to understand how cells use various protein quality control (PQC) strategies to maintain protein homeostasis, and how defects in these processes lead to aging-associated neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Specifically, we study the molecular mechanisms underlying protein translocation-associated quality control at the endoplasmic reticulum (ER), the export of misfolded proteins via unconventional protein secretion, and cell-to-cell transmission of misfolded a-Synuclein and Tau aggregates.
1. Role of misfolding-associated protein secretion (MAPS) in neurodegeneration
Many neurodegenerative disease-associated proteins are known to accumulate in the extracellular space in human brains. What causes the release of these neurotoxic proteins from neurons is unknown, neither are the underlying molecular mechanisms. However, what has been clear is that these proteins need to be exported via an unconventional protein secretion (UPS) mechanism because they do not possess a leader sequence required for endoplasmic reticulum (ER)-mediated secretion of conventional protein cargos like insulin and growth factors. My laboratory recently uncovered an UPS pathway termed misfolding-associated protein secretion (MAPS), which uses molecular chaperones such as USP19 and DNAJC5 to concentrate misfolded proteins in late endosomes before releasing them into the extracellular space. In MAPS, cargos need to be translocated from the cytoplasm into the lumen of late endosomes. A major ongoing effort is to elucidate the mechanism by which these proteins are moved across the late endosome membranes.
Another area of research is to determine the link between MAPS and neurodegeneration. We are currently studying the fate of neurotoxic proteins released by the MAPS pathway, the interaction of secreted proteins with target cells (e.g. astrocytes and microglial cells), and the functional consequence associated with deregulation of the MAPS pathway. We apply a variety of modern cell biology and molecular genetic tools to cultured cells, primary neurons, and animal models in order to address these questions.
2. Cell-to-cell transmission of misfolded neurotoxic proteins
Many neurotoxic proteins released into the cell exterior can undergo cell-to-cell transmission. These proteins are usually aggregation-prone. Therefore, their transfer from cell to cell is thought to facilitate the seeding and spreading of protein aggregates, which causes neurodegeneration in diseases such as Alzheimer’s disease and Parkinson’s disease.
The process of intercellular transmission of misfolded proteins is comprised of two steps: the release of misfolded proteins from a donor cell and their uptake by a recipient neuron. My laboratory studies the mechanism by which misfolded protein aggregates such as a-Synuclein fibrils enter human cells, and how they eventually reach the cytoplasm where they could serve as seeds to amplify protein misfolding signals.
3. Mechanism of translocation-associated protein quality control at the ER
As a major PQC system in eukaryotic cells, the ubiquitin proteasome pathway degrades misfolded proteins as soon as they are generated. By doing so, cells can minimize the risk of protein aggregation. Protein misfolding can occur at every step during protein biogenesis, starting from translation at the ribosome. Therefore, protein synthesis in eukaryotic cells is monitored by a PQC pathway that eliminates partially translated nascent chains due to ribosome stalling or prolonged translation pausing. Recent studies have revealed many mechanistic details on this ribosome quality control pathway, particularly for ribosomes translating cytosolic proteins. However, little is known about how cells deal with stalled ribosomes that synthesize ER-targeted proteins, which constitute approximately one third of the total human proteome. When the translation of ER-bound proteins is halted, the partially translated polypeptides will clog the Sec61 translocon, causing a greater harm to cells than cytosolically localized translation stalling events. We are currently using a combination of biochemical and genetic tools to dissect the molecular mechanisms of translocation-associated protein quality control. Specifically, we focus on the role of a small ubiquitin modifier named UFM1 in this process.
Applying our Research
Intercellular transfer of misfolded proteins such as a-Synuclein and Tau contributes to the pathogenesis of many neurodegenerative diseases including Parkinson’s disease and Alzheimer’s disease, but the molecular mechanisms underlying this prion-like protein behavior is unclear. Defects in translocation-associated protein quality control have been linked to anemia and abnormal neuronal development, but little is known about how cells remove proteins clogged in the Sec61 translocon. We envision that a thorough characterization of these protein quality control systems may one day improve both diagnosis and treatment of aging-associated neurodegenerative diseases.
Need for Further Study
In addition to the elucidating the cellular mechanisms that govern protein homeostasis, we also need to carry out more animal-based studies to better evaluate the physiological roles of these PQC systems in vivo. We will also develop in vitro assays for small molecule inhibitor screens, so we can have better tools to fine-tune these biological processes.
- Postdoctoral Fellow, Harvard Medical School, 2000-2005
- Ph.D., University of Pennsylvania, 2000
- Bachelor of Medicine, Peking University, 1995
Wang Q, Liu Y, Soetandyo N, Baek K, Hegde R, Ye Y. A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation. Mol Cell. 2011;42(6):758-70.
Lee JG, Baek K, Soetandyo N, Ye Y. Reversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells. Nat Commun. 2013;4:1568.
Lee JG, Takahama S, Zhang G, Tomarev SI, Ye Y. Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells. Nat Cell Biol. 2016;18(7):765-76.
Wang L, Xu Y, Rogers H, Saidi L, Noguchi CT, Li H, Yewdell JW, Guydosh NR, Ye Y. UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis. Cell Res. 2020;30(1):5-20.
Zhang Q, Xu Y, Lee J, Jarnik M, Wu X, Bonifacino JS, Shen J, Ye Y. A myosin-7B-dependent endocytosis pathway mediates cellular entry of α-synuclein fibrils and polycation-bearing cargos. Proc Natl Acad Sci U S A. 2020;117(20):10865-10875.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
Genetics and Genomics
This page was last updated on October 15th, 2020