ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

Abstract

Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans. OverviewApproximately one-third of all proteins encoded by the mammalian genome are exported from the endoplasmic reticulum (ER) and transported to the Golgi apparatus, where they are sorted for delivery to their final destination in membrane compartments or secretory vesicles [1]. Secretory proteins are co-translationally inserted into the ER and then packaged into transport vesicles at ER exit sites (ERES, also known as the transitional ER), which are specialized regions of smooth ER [1].The stepwise process for segregating and exporting cargo from the ER is similar in yeast, plant, and mammalian cells and relies on several essential proteins (SAR1-GTPase, SEC23, SEC24, SEC13, and SEC31). The first step involves the conversion of SAR1-GDP to SAR1-GTP by the guanine nucleotide exchange factor SEC12, which resides in the ER membrane [2,3]. This results in the localization of SAR1-GTP to the ER membrane, triggering the recruitment of SEC23/24 heterodimers [4]. The membrane localization of the SEC23/24 heterodimers promotes the entrapment of cargo by SEC24 and the recruitment of SEC13/31 heterotetramers. The sequential binding of SEC13/31 heterotetramers to SAR1-GTP-SEC23/24 complexes drives the formation of a cage-like lattice [4][5][6][7]. Although the basic steps involved in generating COPII vesicles are well understood and can be reconstituted in vitro, additional proteins are involved in regulating the process in cells. Differences between yeast and mammalian ER-to-Golgi trafficking include the presence of multiple COPII protein isoforms and an ER-Golgi intermediate compartment (ERGIC) in mammals, which likely evolved to help meet the cell-type-specific demands of multicellular organisms.Unlike other cell types, neurons consist of two compartments: the somatodendritic compartment and the axonal compartment. These compartments are separated by the axonal-exclusion zone located at the base of the axon, where proteins are either permitted into or excluded from the axon. Neurons are

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

“…While disruption of ER-to-Golgi trafficking is known to result in at least 10 different neurological disorders ( 47 ), its involvement in the etiology of diabetes has been less clear. Recently a truncating mutation in the TANGO1 ( MIA3 ) gene, encoding a protein involved in the export of bulky cargos from the ER to the Golgi, has been reported in one consanguineous family with a complex syndrome of dentinogenesis imperfecta, short stature, skeletal abnormalities, sensorineural hearing loss, and mild intellectual disability.…”

Export Control: Post-transcriptional Regulation of the COPII Trafficking Pathway

“…The COPII pathway is essential for protein sorting and cell viability in a wide range of organisms ( Gomez-Navarro and Miller, 2016 ; Aridor, 2018 ; Bethune and Wieland, 2018 ; Brandizzi, 2018 ; Hutchings and Zanetti, 2019 ; Peotter et al, 2019 ). In humans, genetic defects in COPII impair cargo trafficking and cause a variety of diseases, including skeletal dysplasias, hematologic abnormalities and neurological disorders ( Jones et al, 2003 ; Zhang et al, 2003 ; Boyadjiev et al, 2006 ; Lang et al, 2006 ; Fromme et al, 2007 ; Schwarz et al, 2009 ; Merte et al, 2010 ; Routledge et al, 2010 ; Wansleeben et al, 2010 ; Khoriaty et al, 2012 ; Beetz et al, 2013 ; Brandizzi and Barlowe, 2013 ; Miller and Schekman, 2013 ; Garbes et al, 2015 ; Moosa et al, 2015 ; Wang et al, 2020 ). These examples demonstrate that COPII function is required for tissue and organismal health.…”

Dysregulated Plasma Membrane Turnover Underlying Dendritic Pathology in Neurodegenerative Diseases

“…Thus, it is possible that when endocytic and secretory functions are under assault in neurons, the canonical system may need to limit its purview in dendrites to support its somatic functions. We posit several reasons in support of this possibility: (1) knockdown of Sec31 and nuclear polyQ expression lead to the loss of GOPs, but not somatic Golgi (Chung et al, 2017); (2) loss-of-function mutations of genes related to ER-to-Golgi trafficking, such as Sec31, Rab1, and Sar1, all lead to impaired arborization of dendrites, but normal morphology of axons in Drosophila da neurons (Ye et al, 2007); (3) a partial loss-of-function in Golgi SNARE protein Membrin causes neuron-specific dysfunctions and significantly impairs dendritic growth in a Drosophila model for progressive myoclonus epilepsy (Praschberger et al, 2017); (4) neurons often undergo dendritic degeneration before cell death in NDs (Klapstein et al, 2001;Jaworski et al, 2011;Fogarty et al, 2016); (5) shrinking dendritic area has been identified as an adaptive response to SCA1 toxicity (Dell'Orco et al, 2015); (6) dendrites in Drosophila motoneurons (Ryglewski et al, 2014) and da neurons (Shorey et al, 2020) have been shown to be dispensable for neuronal survival; and (7) endocytic and secretory dysfunctions are often observed in a number of NDs (Wang et al, 2020). These results may partly explain the fact that neuronal dendrites are more vulnerable to neurotoxicity than other neuronal domains (Luebke et al, 2010;Hasel et al, 2015;Kweon et al, 2017).…”