Table1_PEX19 Coordinates Neutral Lipid Storage in Cells in a Peroxisome-Independent Fashion.XLSX

Cellular lipid metabolism is tightly regulated and requires a sophisticated interplay of multiple subcellular organelles to adapt to changing nutrient supply. PEX19 was originally described as an essential peroxisome biogenesis factor that selectively targets membrane proteins to peroxisomes. Metabolic aberrations that were associated with compromised PEX19 functions, were solely attributed to the absence of peroxisomes, which is also considered the underlying cause for Zellweger Spectrum Disorders. More recently, however, it was shown that PEX19 also mediates the targeting of the VCP/P97-recuitment factor UBXD8 to the ER from where it partitions to lipid droplets (LDs) but the physiological consequences remained elusive. Here, we addressed the intriguing possibility that PEX19 coordinates the functions of the major cellular sites of lipid metabolism. We exploited the farnesylation of PEX19 and deciphered the organelle-specific functions of PEX19 using systems level approaches. Non-farnesylated PEX19 is sufficient to fully restore the metabolic activity of peroxisomes, while farnesylated PEX19 controls lipid metabolism by a peroxisome-independent mechanism that can be attributed to sorting a specific protein subset to LDs. In the absence of this PEX19-dependent LD proteome, cells accumulate excess triacylglycerols and fail to fully deplete their neutral lipid stores under catabolic conditions, highlighting a hitherto unrecognized function of PEX19 in controlling neutral lipid storage and LD dynamics.

细胞脂质代谢受到严格调控，需要多个亚细胞器之间复杂的相互作用以适应不断变化的营养供应。PEX19最初被描述为一种必需的过氧化物酶体生物发生因子，能够选择性地将膜蛋白靶向至过氧化物酶体。与PEX19功能受损相关的代谢异常，被归因于过氧化物酶体的缺失，这也被认为是Zellweger综合征谱系疾病的潜在原因。然而，最近的研究表明，PEX19还介导VCP/P97募集因子UBXD8从内质网靶向至脂滴（LDs），但其生理学后果尚不明确。在本研究中，我们探讨了PEX19可能协调细胞中主要脂质代谢位点功能的迷人可能性。我们利用了PEX19的异戊二烯化作用，并采用系统级方法解析了PEX19的细胞器特异性功能。非异戊二烯化PEX19足以完全恢复过氧化物酶体的代谢活性，而异戊二烯化PEX19通过过氧化物酶体非依赖性机制控制脂质代谢，这种机制可归因于将特定的蛋白质子集排序至脂滴。在没有这种PEX19依赖性脂滴蛋白质组的情况下，细胞在分解代谢条件下积累过多的三酰甘油，并无法完全耗尽其中性脂质储备，突显了PEX19在控制中性脂质储存和脂滴动态中的先前未被认识到的功能。