Jin Ye Lab


Lipid-Mediated Signaling Reactions in Health and Disease

Lipids are key components of our life. They maintain structural integrity and supply energy for the survival of our cells. The lipid-protein interactions discovered recently suggest that lipids also play a critical role in signal transduction, a function that has been underappreciated. My lab is broadly interested in lipid-mediated signaling reactions. Currently, we are focusing on ferroptosis, a cell death pathway triggered by Fe2+-catalyzed peroxidation of polyunsaturated fatty acids (PUFAs) in phospholipids, and ceramide-induced topological regulation of transmembrane proteins.

Our interest in ferroptosis stems from our study of a family of proteins that contain the UAS domain, a motif interacting with unsaturated but not saturated, free but not esterified fatty acids. FAF1, a protein belonging to this family, is crucial to protect cells from ferroptosis. The interaction between unsaturated free fatty acids (FFAs) and FAF1 results in assembly of a membraneless organelle we designated as FFAsome with radiuses ranging from 50 to 200 nm. The surface of FFAsome is coated by clusters of FAF1 proteins whereas the hydrophobic interior of the organelle contains FFA aggregates (Fig. 1). Sequestration of free PUFAs such as arachidonic acid (AA) into the hydrophobic core of FFAsome limits their access to Fe2+, thereby protecting cells from ferroptosis (Fig. 1). Thus, cells deficient in FAF1 did not survive when they were exposed to physiological levels of PUFAs, and mice with liver-specific knockout of Faf1 developed acute hepatitis upon consuming a diet enriched in AA.

An interesting question raised by this study is how FFAs are packaged by FAF1 into FFAsome. In the absence of any protein, FFAs by themselves are assembled into a structure similar to FFAsome only under acidic pH, a condition allowing the FFA to exist as uncharged protonated form (R-COOH) that could spontaneously aggregate in aqueous solution owing to its hydrophobicity. In contrast, this structure is not generated under physiological pH because the FFA primarily exists as hydrophilic negatively charged anions (R-COO-). Thus, FAF1 may catalyze formation of FFAsome by serving as an enzyme that transfers protons to unsaturated FFAs under physiological pH. If so, FAF1 will be the first enzyme identified with such an activity.

FAF1 protects cells Fig. 1. FAF1 protects cells from ferroptosis through assembly of FFAsome.

A major obstacle in studying ferroptosis is the lack of a marker that can identify ferroptotic cells under physiological conditions. To solve this problem, we recently identified hyperoxidized PRDX3 as a marker for ferroptosis. Using this marker, we determined that hepatic injury in alcoholic liver disease (ALD) is caused by ferroptosis. ALD is one of the most prevalent chronic liver diseases in the United States. There is currently no effective treatment for ALD, as the mechanism through which excess consumption of alcohol leads to death of hepatocytes has not been uncovered. Our findings that hepatic injury in ALD is caused by ferroptosis provide new opportunities to improve the current animal model for ALD and enable development of new strategies to treat the disease.

Another area of interest in my lab is topological regulation of transmembrane proteins. This project stems from our study of signaling reactions that activate a transcription factor called CREB3L1. Unlike typical transcription factors, CREB3L1 is synthesized as a membrane-bound precursor. Under resting conditions, CREB3L1 remains as the inactive precursor through the action of TM4SF20, a polytopic transmembrane protein. Upon ceramide accumulation, CREB3L1 is subject to proteolysis that releases the NH2-terminal domain of the protein from membranes, allowing it to enter nucleus where it activates transcription of genes that inhibit progression of cell cycle. Remarkably, ceramide activates CREB3L1 by altering the topology of TM4SF20, a process turning TM4SF20 from an inhibitor to an activator for cleavage of CREB3L1 (Fig. 2). Recently, we determined that in the absence of ceramide, the topology of mature TM4SF20 is different from that of the protein originally synthesized owing to retrotranslocation of sequence containing an N-linked glycosylation site from lumen to cytosol. Ceramide alters the topology of TM4SF20 by inhibiting this retrotranslocation process, leading to accumulation of the protein that is originally synthesized (Fig. 2).

TM4SF20 Fig. 2. Ceramide-regulated topological alteration of TM4SF20

This astonishing discovery challenges the assumption that transmembrane proteins should adopt a fixed topology after their synthesis in the ER. Instead, we demonstrate that topological alteration could be a novel mechanism to regulate transmembrane proteins. This mechanism is not restricted to TM4SF20, as ceramide also alters the topology of CCR5, a G protein-coupled receptor. Moreover, the identification of TM4SF20 as a protein with an N-glycan at the cytosolic side of membranes challenges the textbook dogma that N-glycans are restricted in luminal or extracellular side of membranes. Thus, the continuation of the project on topological regulation of transmembrane proteins may revolutionize our understanding of cell biology.

Meet the PI & Lab Members

Portrait of Dr. Jin Ye

Jin Ye, Ph.D.

Jin Ye received a MS degree in Biochemistry from Case Western Reserve University in 1995. He was mentored by Nobel laureates Michael Brown and Joseph Goldstein at UT Southwestern, obtaining his PhD in Cell Regulation in 2000, and continuing in a postdoctoral fellowship from 2000 to 2004.He joined the faculty at the UT Southwestern Medical Center in 2004 as an Assistant Professor. He was promoted to Professor in 2022.

Shaojie Cui

Senior Research Scientist

Yaqin Deng

Postdoctoral Researcher

Kosuke Kamemura

Postdoctoral Researcher

Lori Nguyen

Research Associate

Contact Us

Phone: 214-648-3461

Mailing Address
Department of Molecular Genetics
UT Southwestern Medical Center
5323 Harry Hines Blvd.
Dallas, TX 75390-9046

Physical Address