PEX19 Coordinates Neutral Lipid Storage in Cells in a Peroxisome-Independent Fashion.
PEX19 Coordinates Neutral Lipid Storage in Cells in a Peroxisome-Independent Fashion.
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DOI：
10.3389/fcell.2022.859052
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
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细胞的脂质代谢受到严格的调控，需要多个亚细胞细胞器复杂的相互作用来适应不断变化的营养供应。PEX19最初被描述为一种重要的过氧酶体生物发生因子，它选择性地将膜蛋白靶向过氧酶体。与PEX19功能受损相关的代谢异常完全归因于过氧体的缺乏，这也被认为是Zellweger谱系疾病的潜在原因。然而，最近的研究表明，PEX19还介导VCP/P97-恢复因子UBXD8靶向内质网，从那里它分割到脂滴(LDS)，但其生理后果仍然难以捉摸。在这里，我们提出了一个有趣的可能性，即PEX19协调脂代谢的主要细胞部位的功能。我们利用了PEX19的法尼化作用，并使用系统水平的方法破译了PEX19的细胞器特异性功能。非法呢化的PEX19足以完全恢复过氧化体的代谢活性，而法尼化的PEX19通过一种不依赖于过氧酶体的机制来控制脂质代谢，这种机制可以归因于将特定的蛋白质亚集分选到LDS。在缺乏这种依赖于PEX19的LD蛋白质组的情况下，细胞积累过量的三酰甘油，并在分解代谢条件下无法完全耗尽其中性脂肪储存，这突显了PEX19在控制中性脂肪储存和LD动力学方面迄今未被认识到的功能。
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.
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影响因子：
11.8
作者：
Kory N;Thiam AR;Farese RV Jr;Walther TC
通讯作者：
Walther TC
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5.5
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Wanders RJ;Waterham HR;Ferdinandusse S
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Ferdinandusse S
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4.8
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Rucktaeschel, Robert;Thoms, Sven;Erdmann, Ralf
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Erdmann, Ralf
影响因子：
14.9
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Perez-Riverol Y;Bai J;Bandla C;García-Seisdedos D;Hewapathirana S;Kamatchinathan S;Kundu DJ;Prakash A;Frericks-Zipper A;Eisenacher M;Walzer M;Wang S;Brazma A;Vizcaíno JA
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Vizcaíno JA
影响因子：
4.6
作者：
Lauer AA;Janitschke D;Dos Santos Guilherme M;Nguyen VTT;Bachmann CM;Qiao S;Schrul B;Boehm U;Grimm HS;Hartmann T;Endres K;Grimm MOW
通讯作者：
Grimm MOW