Why we care about the lysosomes?

The lysosome is a central catabolic station that breaks down and recycles cellular materials to maintain nutrient homeostasis. It also plays a vital role in nutrient sensing and intracellular signaling through the mTORC1 complex (Fig.1A). During aging, lysosome dysfunction will lead to the accumulation of protein aggregates, inefficient organelle, and high sensitivity to cell stress. All these problems will eventually cause neuron cell dysfunction and death, resulting in neurodegeneration such as Alzheimer’s and Parkinson’s diseases (Fig.1B). On the other hand, cancer cells frequently up-regulate their lysosomal catabolic activity to fuel uncontrolled growth (Fig.1C). In addition, the mutations in lysosomal genes will directly lead to ~ 70 different lysosomal storage diseases (LSDs). Despite its importance, very little is known about how lysosome biogenesis and composition are dynamically regulated according to environmental cues.

Our laboratory uses a combination of molecular biology, cell biology, genetics, and biochemistry approaches to explore the fundamental and physiological role of lysosome dynamics in the context of aging-related neurodegeneration, cancer, and LSDs. Our goal is to uncover new findings that will stand the test of time, and eventually help developing the new therapeutic strategies.

How does lysosome regulate its membrane composition?

To maintain the nutrient homeostasis, many membrane transporters are present on the lysosomal membrane that can transport nutrients in and out of lysosome. However, how these transporters are properly regulated, especially how do the cells remove the unneeded lysosomal membrane proteins is still an open question. Using budding yeast and mammalian cells as model systems, we discovered a conserved ubiquitin- and ESCRT-dependent microautophagy pathway to degrade lysosome membrane proteins.

In yeast cells, we surprisingly observed that many vacuole (yeast lysosome) membrane (VM) proteins are degraded in response to TORC1 inactivation (Left Top Movie). We further dissected the participating molecular machinery, and found that LMPs are ubiquitinated during TORC1 inactivation, and then sent into lysosome lumen for degradation by the ESCRT machinery(Left Bottom Model). Lastly, we found that this ubiquitin (E3 ligase)- and ESCRT-dependent pathway is also conserved in mammalian cells (Left Bottom Model).

The current focus of this research direction includes: 1) Novel pathways and machineries involved in lysosome membrane protein quality control; 2) Human lysosome harbors hundreds of membrane proteins and dozens of E3 ligases, what is each E3 specifically recognizing; and 3) How does the cell regulate the activity of the quality control machineries, such as E3 ligases.

How does cell regulate lysosome biogenesis?

To identify genes important for lysosome function, we conducted a a genome-wide CRISPR-Cas9 knockout screening, and unexpectedly discovered TMEM251, a gene of unknown function (Fig.3A).

Why TMEM251 is important for lysosome function? Our further studies uncovered that TMEM251 gene encodes a small Golgi membrane protein, and plays an essential role in the Mannose-6-phosphate (M6P)-dependent sorting of lysosomal enzymes (Fig.3B). Without TMEM251, most lysosomal enzymes lose their M6P modification and can no longer be delivered to the lysosome. Instead, they are secreted out of the cells and lead to the lysosome dysfunction inside the cell. In human, patients carrying TMEM251 mutations will develop a very severe lysosomal storage disease, which we named as Mucolipidosis Type V. Furthermore, based on the fundamental knowledge we learned from the function of TMEM251, we proposed a Enzyme replacement therapy (ERT) to treat TMEM251 deficiency (Fig. 3C).

The current focus of this research direction includes: 1) what is the pathogenesis mechanism for TMEM251 patient variant ? 2) How does the cell regulate the activity of the M6P biogenesis pathway? 3) Novel pathways and genes important for lysosome biogenesis and function.