Hall Riley, Sawant Vallari, Gu Jinchao, Sikora Tim, Rollo Ben, Velasco Silvia, Kim Jinkuk, Segev Nava, Christodoulou John, Van Bergen Nicole J
Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
Int J Mol Sci. 2024 Dec 12;25(24):13329. doi: 10.3390/ijms252413329.
The TRAPP (TRAnsport Protein Particle) protein complex is a multi-subunit complex involved in vesicular transport between intracellular compartments. The TRAPP complex plays an important role in endoplasmic reticulum-to-Golgi and Golgi-to-plasma membrane transport, as well as autophagy. TRAPP complexes comprise a core complex, TRAPPI, and the association of peripheral protein subunits to make two complexes, known as TRAPPII and TRAPPIII, which act as Guanine Nucleotide Exchange Factors (GEFs) of Rab11 and Rab1, respectively. Rab1 and Rab11 are GTPases that mediate cargo selection, packaging, and delivery during pre- and post-Golgi transport in the secretory pathway. Rab1 is also required for the first step of macroautophagy, a cellular recycling pathway. Pathogenic variants in genes encoding protein subunits of the TRAPP complex are associated with a range of rare but severe neurological, skeletal, and muscular disorders, collectively called TRAPPopathies. Disease-causing variants have been identified in multiple subunits of the TRAPP complex; however, little is known about the underlying disease mechanisms. In this review, we will provide an overview of the current knowledge surrounding disease-associated variants of the TRAPP complex subunits, propose new insights into the underlying disease pathology, and suggest future research directions into the underlying disease mechanisms.
TRAPP（转运蛋白颗粒）蛋白复合物是一种多亚基复合物，参与细胞内区室之间的囊泡运输。TRAPP复合物在内质网到高尔基体以及高尔基体到质膜的运输以及自噬过程中发挥重要作用。TRAPP复合物包括一个核心复合物TRAPPI，以及外周蛋白亚基的结合形成两种复合物，即TRAPPII和TRAPPIII，它们分别作为Rab11和Rab1的鸟嘌呤核苷酸交换因子（GEF）。Rab1和Rab11是GTP酶，在分泌途径中高尔基体前和高尔基体后的运输过程中介导货物的选择、包装和递送。Rab1也是细胞自噬（一种细胞回收途径）第一步所必需的。编码TRAPP复合物蛋白亚基的基因中的致病变体与一系列罕见但严重的神经、骨骼和肌肉疾病相关，统称为TRAPP病。已在TRAPP复合物的多个亚基中鉴定出致病变体；然而，对潜在的疾病机制了解甚少。在本综述中，我们将概述围绕TRAPP复合物亚基疾病相关变体的当前知识，对潜在的疾病病理学提出新的见解，并提出未来对潜在疾病机制的研究方向。
