Lyschik Sven, Lauer Anna A, Roth Tanja, Janitschke Daniel, Hollander Markus, Will Thorsten, Hartmann Tobias, Kopito Ron R, Helms Volkhard, Grimm Marcus O W, Schrul Bianca
Medical Biochemistry and Molecular Biology, Center for Molecular Signaling (PZMS), Faculty of Medicine, Saarland University, Homburg, Germany.
Experimental Neurology, Saarland University, Homburg, Germany.
Front Cell Dev Biol. 2022 Apr 26;10:859052. doi: 10.3389/fcell.2022.859052. eCollection 2022.
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来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，它能将膜蛋白选择性地靶向到过氧化物酶体。与PEX19功能受损相关的代谢异常，仅归因于过氧化物酶体的缺失，这也被认为是泽尔韦格谱系障碍的根本原因。然而，最近有研究表明，PEX19还介导VCP/P97招募因子UBXD8从内质网靶向到脂滴（LDs），但其生理后果仍不清楚。在这里，我们探讨了PEX19协调脂质代谢主要细胞位点功能这一有趣的可能性。我们利用了PEX19的法尼基化，并使用系统水平的方法来解读PEX19在细胞器特异性方面的功能。未进行法尼基化的PEX19足以完全恢复过氧化物酶体的代谢活性，而进行了法尼基化的PEX19则通过一种不依赖过氧化物酶体的机制来控制脂质代谢，这种机制可归因于将特定的蛋白质亚群分选到脂滴中。在缺乏这种依赖PEX19的脂滴蛋白质组的情况下，细胞会积累过量的三酰甘油，并且在分解代谢条件下无法完全耗尽其中性脂质储存，这突出了PEX19在控制中性脂质储存和脂滴动态方面迄今未被认识到的功能。
