TRAPPopathies: Severe Multisystem Disorders Caused by Variants in Genes of the Transport Protein Particle (TRAPP) Complexes

Abstract

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.

Keywords: Rab GTPase; TRAPP complex; autophagy; human genetics; intracellular trafficking; neurological disease; pediatrics.

Figure 3

TRAPP complex and disease associations. Pathogenic variants in protein subunits of the core (TRAPPC2L, TRAPPC4, and TRAPPC6) and subunits specific to the two TRAPP complexes, TRAPPII (TRAPPC9 and TRAPPC10) and TRAPPIII (TRAPPC11 and TRAPPC12), are associated with neurodevelopmental disorders. In addition, pathogenic variants in TRAPPC11 are also involved in Limb Girdle Muscular Dystrophy. Dysregulation of TRAPPC4 and TRAPPC9 also occurs in cancer. The only subunits associated with a clinically distinct phenotype are pathogenic variants in TRAPPC2, part of the TRAPP core complex, causing a distinct skeletal disorder, Spondyloepiphyseal Dysplasia Tarda (SEDT). TRAPP complex composition adapted from [114]. Created in BioRender [115].

Figure 1

Stages of the vesicular transport pathway in which TRAPPII and TRAPPIII and their respective Rab GTPases are involved. The TRAPPIII complex is a Guanine Exchange Factor (GEF) for Rab1, which mediates early stages of the vesicular transport pathway from the endoplasmic reticulum (ER) to the Golgi apparatus and formation of autophagosome membranes prior to fusion with lysosomes into the autolysosome. The TRAPPII complex is a GEF for Rab11 and mediates the Golgi-to-plasma membrane stage of the secretory pathway. Created in BioRender [18].

Figure 2

The role of TRAPPC4 and TRAPPC9 in cell signaling. TRAPPC4 (Synbindin) is involved in the Ras-Raf-Mek-ERK signaling pathway. RAS translocates from the plasma membrane to the Golgi where association with GRP1 promotes a phosphorylation cascade of MEK and ERK. TRAPPC4 binds to MEK1 and ERK in the Golgi after phosphorylation of ERK2 by MEK and activation of nuclear and cytoplasmic ERK targets [52]. ERK targets cause enhanced cell proliferation and migration in cancer [55]. TRAPPC9 functions within the NFκB pathway by binding to NIK and IKK2, leading to phosphorylation of IKK1, which then phosphorylates P100, promoting P100 cleavage and processing of P100 to P52, which, in conjunction with RelB, forms the activated NFκB complex [52,55,56,57]. Figure adapted from [52,58] and created in BioRender [59].