LMA-2对溶酶体形态及功能调控的研究

Lysosomes are ubiquitous membrane-bound intracellular organelles that degrade macromolecules delivered by endocytosis, phagocytosis, and autophagy, and export the resulting catabolites for reutilization in cellular metabolism. In addition to cargo digestion and recycling, lysosomes are being recognized as advanced organelles that perform much broader functions and are involved in fundamental cellular processes such as plasma membrane repair, immune response, nutrient sensing and signaling, and cell death. Impairment of lysosome function contributes to the pathogenesis of many diseases including lysosomal storage diseases, neurodegenerative disorders and cancer. ..Lysosomes are observed as globular or tubular structures. The morphological change of lysosomes may associate with specific cellular processes. For example, tubular lysosomes are observed in macrophages that engulf invading bacterial, and in the process of ALR when lysosomes are reformed from autolysosomes. These studies indicate that lysosomal morphology may be tightly controlled to fulfill specific functions. Using C. elegans as a model organism, we performed a large-scale genetic screen to search for mutants that contain extensive tubular lysosomes. From this screen, we identified lma-2 (lysosomal morphology abnormal 2), whose loss-of-function causes extensive tubulation of the lysosome. lma-2 mutants cause defects in larval development and the shortened adult lifespan. We will employ combined approaches of genetics, cell biology and biochemistry to elucidate how LMA-2 regulates lysosome morphology and function and how this contribute to larval development and lifespan regulation.

溶酶体位于多个细胞途径的下游，负责物质降解和循环。由溶酶体缺陷引起的代谢及神经退行性疾病的发现和研究充分证明了溶酶体在机体发育及维持代谢稳态平衡中的关键作用。溶酶体多以球形形态存在，只在很少的情况下能观察到管状溶酶体。例如，巨噬细胞吞噬物体时细胞中会产生大量的管状溶酶体结构，而近期的研究发现溶酶体由自噬溶酶体的再生也伴随着管状结构的形成，表明溶酶体形态的变化可能受到了精确的调控。利用遗传筛选，我们获得了多个参与调控溶酶体形态及动态变化的基因，并成功地克隆了其中的一个基因，命名为LMA-2。该基因的突变导致细胞中累积大量的管状溶酶体并形成致密的网状结构。该突变体的寿命相对于野生型明显缩短，并表现线虫发育缺陷，表明溶酶体形态功能的正常维持对线虫发育及寿命维持具有重要作用。我们将以线虫为模式研究LMA-2在溶酶体形态，功能及动态变化调控中的作用机制。