Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism.
Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism.
复制标题
DOI：
10.1016/j.jbc.2023.105013
复制
发表时间：
2023-08
影响因子：
4.8
通讯作者：
Schrader, Michael
中科院分区：
文献类型：
--
作者：
Costello, Joseph L.;Koster, Janet;Silva, Beatriz S. C.;Worthy, Harley L.;Schrader, Tina A.;Hacker, Christian;Passmore, Josiah;Kuypers, Frans A.;Waterham, Hans R.;Schrader, Michael
过氧化物酶体和内质网（ER）是紧密相连的亚细胞器，在膜接触部位物理连接。虽然在脂质代谢，例如，极长链脂肪酸（VLCFAs）和缩醛磷脂的合作，ER也发挥了过氧化物酶体生物合成的作用。最近的工作确定了连接细胞器的ER和过氧化物酶体膜上的拴系复合物。这些包括通过ER蛋白VAP B（囊泡相关膜蛋白相关蛋白B）和过氧化物酶体蛋白ACBD 4和ACBD 5（酰基辅酶A结合结构域蛋白）之间的相互作用形成的膜接触。ACBD 5的缺失已显示导致过氧化物酶体-ER接触和VLCFA积累的显著减少。然而，ACBD 4的作用和这两种蛋白质对接触位点形成和VLCFA向过氧化物酶体的募集的相对贡献仍不清楚。在这里，我们使用分子细胞生物学、生物化学和脂质组学分析的组合来解决这些问题，这些分析是在HEK 293细胞中ACBD 4或ACBD 5丢失后进行的。我们发现ACBD 5的拴系功能对于VLCFA的有效过氧化物酶体β-氧化不是绝对必需的。我们证明，ACBD 4的损失不会减少过氧化物酶体-ER连接或导致VLCFA的积累。相反，ACBD 4的丢失导致VLCFA的β-氧化速率增加。最后，我们观察到ACBD 5和ACBD 4之间的相互作用，独立于VAPB结合。总体而言，我们的研究结果表明，ACBD 5可能作为一个主要的系链和VLCFA招募因子，而ACBD 4可能在过氧化物酶体-ER界面的过氧化物酶体脂质代谢中具有调节功能。
Peroxisomes and the endoplasmic reticulum (ER) are intimately linked subcellular organelles, physically connected at membrane contact sites. While collaborating in lipid metabolism, for example, of very long-chain fatty acids (VLCFAs) and plasmalogens, the ER also plays a role in peroxisome biogenesis. Recent work identified tethering complexes on the ER and peroxisome membranes that connect the organelles. These include membrane contacts formed via interactions between the ER protein VAPB (vesicle-associated membrane protein-associated protein B) and the peroxisomal proteins ACBD4 and ACBD5 (acyl-coenzyme A-binding domain protein). Loss of ACBD5 has been shown to cause a significant reduction in peroxisome–ER contacts and accumulation of VLCFAs. However, the role of ACBD4 and the relative contribution these two proteins make to contact site formation and recruitment of VLCFAs to peroxisomes remain unclear. Here, we address these questions using a combination of molecular cell biology, biochemical, and lipidomics analyses following loss of ACBD4 or ACBD5 in HEK293 cells. We show that the tethering function of ACBD5 is not absolutely required for efficient peroxisomal β-oxidation of VLCFAs. We demonstrate that loss of ACBD4 does not reduce peroxisome–ER connections or result in the accumulation of VLCFAs. Instead, the loss of ACBD4 resulted in an increase in the rate of β-oxidation of VLCFAs. Finally, we observe an interaction between ACBD5 and ACBD4, independent of VAPB binding. Overall, our findings suggest that ACBD5 may act as a primary tether and VLCFA recruitment factor, whereas ACBD4 may have regulatory functions in peroxisomal lipid metabolism at the peroxisome–ER interface.
登录
查看更多内容
DOI：
10.1083/jcb.201608128
发表时间：
2017-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hua R;Cheng D;Coyaud É;Freeman S;Di Pietro E;Wang Y;Vissa A;Yip CM;Fairn GD;Braverman N;Brumell JH;Trimble WS;Raught B;Kim PK
通讯作者：
Kim PK
DOI：
10.1073/pnas.1611096114
发表时间：
2017-02-14
影响因子：
11.1
作者：
Hoeglinger, Doris;Nadler, Andre;Schultz, Carsten
通讯作者：
Schultz, Carsten
影响因子：
4
作者：
Ferdinandusse, Sacha;Falkenberg, Kim D.;Waterham, Hans R.
通讯作者：
Waterham, Hans R.
DOI：
10.1080/15384101.2017.1314422
发表时间：
2017-06-03
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Costello JL;Castro IG;Schrader TA;Islinger M;Schrader M
通讯作者：
Schrader M
影响因子：
82.9
作者：
Kemp, S;Wei, HM;Smith, KD
通讯作者：
Smith, KD