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Last update 23 Jan 2025

SLC35A1

Last update 23 Jan 2025

Basic Info

Synonyms

CMP-SA-Tr, CMP-Sia-Tr, CMP-sialic acid transporter

+ [6]

Introduction

Transports CMP-sialic acid from the cytosol into the Golgi apparatus, functioning as an antiporter that exchanges CMP-sialic acid for CMP (PubMed:15576474, PubMed:12682060, PubMed:23873973). Binds both CMP-sialic acid and free CMP, but has higher affinity for free CMP (By similarity). Also able to exchange CMP-sialic acid for AMP and UMP (PubMed:12682060). Also mediates the transport of CDP-ribitol (By similarity).

Drugs associated with SLC35A1

KI-8110

Target

SLC35A1

Mechanism

SLC35A1 inhibitors

Active Org.-

Originator Org.

Mect Corp.

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with SLC35A1

100 Translational Medicine associated with SLC35A1

0 Patents (Medical) associated with SLC35A1

156

Literatures (Medical) associated with SLC35A1

08 Jan 2025·mBio

Identification of SLC35A1 as an essential host factor for the transduction of multi-serotype recombinant adeno-associated virus (AAV) vectors

Article

Author: McFarlin, Shane ; Qiu, Jianming ; Zhang, Xiujuan ; Ning, Kang ; Richart, Donovan ; Feng, Zehua ; Zhang-Chen, Ander ; Yan, Ziying ; McFarlane, Richenda ; Cheng, Fang ; Hao, Siyuan ; Aksu Kuz, Cagla

ABSTRACT We conducted a genome-wide CRISPR/Cas9 screen in suspension 293 F cells transduced with rAAV5. The highly selected genes revealed after two rounds of screening included the previously reported KIAA0319L , TM9SF2 , and RNF121 , along with a cluster of genes involved in glycan biogenesis, Golgi apparatus localization, and endoplasmic reticulum penetration. In this report, we focused on solute carrier family 35 member A1 ( SLC35A1 ), a Golgi apparatus-localized cytidine 5’-monophosphate-sialic acid (CMP-SIA) transporter. We confirmed that SLC35A1 knockout (KO) significantly decreased rAAV5 transduction to a level lower than that observed in KIAA0319L or TM9SF2 KO cells. Although SLC35A1 KO drastically reduced the expression of α2,6-linked SIA on the cell surface, the expression of α2,3-linked SIA, as well as the cell binding and internalization of rAAV5, was only moderately affected. Moreover, SLC35A1 KO significantly diminished the transduction of AAV multi-serotypes, including rAAV2 and rAAV3, which do not utilize SIAs for primary attachment. Notably, the SLC35A1 KO markedly increased transduction of rAAV9 and rAAV11, which primarily attach to cells via binding to galactose. Further analyses revealed that SLC35A1 KO significantly decreased vector nuclear import. More importantly, although the C-terminal cytoplasmic tail deletion (∆C Tail) mutant of SLC35A1 did not drastically decrease SIA expression, it significantly decreased rAAV transduction, as well as vector nuclear import, suggesting that the C-tail is critical in these processes. Furthermore, the T128A mutant significantly decreased SIA expression but still supported rAAV transduction and nuclear import. These findings highlight the involvement of the CMP-SIA transporter in the intracellular trafficking of rAAV vectors post-internalization. IMPORTANCErAAV is an essential tool for gene delivery in the treatment of genetic disorders; however, the mechanisms of rAAV transduction remain partially understood. GPR108 is vital for the transduction of most rAAV vectors, but not for rAAV5. We aimed to identify host factors that impact AAV5 transduction akin to GPR108. Using a genome-wide CRISPR/Cas9 screen in 293 F cells, we identified SLC35A1, a Golgi apparatus-localized CMP-sialic acid transporter that transports CMP-sialic acid from the cytoplasm into the Golgi apparatus for sialylation, is essential to rAAV transduction. Further studies across various AAV serotypes showed SLC35A1 significantly affects vector nuclear import post-internalization. These results underscore the crucial role of SLC35A1 in intracellular trafficking beyond the initial cell attachment of rAAV.

24 Dec 2024·ACS Omega

Structure–Function Relationships of the CMP-Sialic Acid Transporter through Analysis of a Pathogenic Variant in an Alternatively Spliced Functional Isoform

Article

Author: Domínguez-Mendoza, Blanca E. ; Velázquez-Dodge, Brenda I. ; Martínez-Duncker, Iván ; Pérez-Cervera, Yobana ; Mora-Montes, Héctor M. ; Ramírez-Martínez, Marco A. ; Pastor, Nina ; Salinas-Marín, Roberta

The human CMP-sialic acid transporter (hCST) is a mammalian highly conserved type III antiporter that translocates CMP-sialic acid into the Golgi lumen, supporting sialylation. Although different works have focused on elucidating structure-function relationships in the hCST, this is the first study to address them in an alternatively spliced isoform. We have previously reported the expression of a functional human del177 isoform that has skipping of exon 6, resulting in a loss of 59 amino acids, without change in the open reading frame and conserving its C-terminal region. To elucidate structure-function relationships, we interrogated this isoform with a known pathogenic variant c.303C>T (p.Q101H) for the wt isoform, showing that its pathogenicity is significatively reduced in the mutated del177 isoform (del177^Q101H). This is further explained by using a homology model based on previously reported mouse and maize crystal structures.

01 Dec 2024·Alzheimer's & Dementia

Analyzing the expression of candidate genes in whole blood of autosomal dominant Alzheimer’s Disease

Article

Author: Antonell, Anna ; Gómez‐Núñez, Alba ; Comas‐Albertí, Aina ; Ramos‐Campoy, Oscar ; Balasa, Mircea ; Bosch, Bea ; Sánchez‐Valle, Raquel ; Pérez‐Millan, Agnès ; Fernandez‐Villullas, Guadalupe ; Lladó, Albert ; Puey, Roger

AbstractBackgroundAutosomal dominant Alzheimer’s Disease (ADAD) represents around 0.5% of all AD cases, and is caused by mutations in PSEN1, PSEN2 and APP genes. Gene expression studies can be useful for unravelling the physiopathology of AD and identifying potential biomarkers. However, most studies are focused on late‐onset AD (LOAD), and mainly on brain tissue or immune cells. Preliminary data from our group showed 9 common differentially expressed genes (DEGs) both in brain tissue and lymphoblastoid cell lines in ADAD versus healthy controls (AMMERCR1L, FMR1, FXYD5, PRR3, RNU2.1, SCARNA2, SLC35A1, TCEAL8, TMEM184B). We aim to investigate these DEGs along with 3 AD relevant genes (APP, PSEN1 and MAPT) in whole blood of ADAD with the goal to explore new potential biomarkers.MethodOur cohort (N = 69) consisted of ADAD symptomatic mutation carriers (SMC; N = 19), asymptomatic mutation carriers (AMC; N = 18) and healthy non carriers (CTRL; N = 32). RNA was extracted from whole blood and relative gene expression was determined by RT‐qPCR and ΔΔCt method. Permutation tests were used to determine the differential gene expression between groups. Additionally, a correlation analysis was performed between estimated years of onset (for AMC) or years since onset (for SMC) and relative expression.ResultDEGs were mainly down‐regulated in ADAD with respect to CTRL, except for FXYD5 and MAPT, which were up‐regulated. When comparing ADAD mutation carriers versus CTRL the significant genes were APP (p = 0.045), FXYD5 (p = 0.018), MAPT (p = 0.041), PSEN1 (p = 5e‐4), SCARNA2 (p = 0.042) and TMEM184B (p = 0.0042) (Fig. 1). Then, we compared AMC versus CTRL and SMC versus CTRL and found two DEGs in both comparisons: FXYD5 (p = 0.015; p = 0.033) and MAPT (p = 0.015; p = 0.034). In AMC group we also found these DEGs: FMR1 (p = 0.011), PRR3 (0.029), PSEN1 (p = 2e‐4), SCARNA2 (p = 0.027) and TMEM184B (p = 5e‐4) (Fig. 2). Results showed a significant negative correlation for RNU2.1 (p = 0.016) and PRR3 (p = 0.029) between relative expression and years since onset in SMC (Fig. 3).ConclusionMutation carriers show some DEGs in whole blood, even in the asymptomatic stage. FXYD5 and MAPT genes show a consistent up‐regulation in both SMC and AMC, suggesting it could be further validated as a possible genetic biomarker in whole blood of ADAD.

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SLC35A1

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