SLC33A1 Membrane Protein Introduction

Introduction of SLC33A1

SLC33A1 is encoded by SLC33A1 gene which is located on 3q25.31 in human. The mutations of the gene can cause autosomal-dominant spastic paraplegia (SPG42) which is a neurodegenerative disorder with weakness and spasticity of the lower limbs. Besides, the mutations of SLC33A1 is also related to congenital cataracts, hearing loss, and neurodegeneration (CCHLND), an autosomal recessive disorder. SLC33A1 belongs to SLC33A transporter family of which members are membrane transport proteins. The molecular mass of SLC33A1 is about 60 KDa.

Function of SLC33A1 Membrane Protein

SLC33A1 is an endoplasmic reticulum membrane protein which is identified in 1997 for the first time and is named AT-1. SLC33A1 is ubiquitously expressed in human, it can be found in placenta, brain, skeletal muscle, lung, liver, heart, kidney and pancreas, with strongest signals in pancreas. Accordingly, SLC33AI mainly acts as an Ac-CoA transporter which plays a crucial role in O-acetylation of gangliosides. It also has solute: proton symporter activity participates in SMAD protein signal transduction, transmembrane transport. What’ s more, SLC33A1 can ensure a continuous supply of acetyl-CoA into the lumen of the endoplasmic reticulum (ER), and Acetyl-CoA levels in the lumen of the ER will influence the induction of autophagy/ERAD(II) during the unfolded protein response (UPR). It has been shown that IRE1/XBP1 regulates the induction of autophagy/ERAD(II) during the UPR by activating SLC33A1. Failure to induce AT-1 leads to widespread cell death. Beyond that, SLC33A1 can negatively regulate BMP signaling.

Fig.1 IRE1/XBP1 regulates the influx of acetyl-CoA into the ER lumen through SLC33A1/AT-1 (Pehar, 2012).

Application of SLC33A1 Membrane Protein in Literature

1. Hullinger R., et al. Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation. Journal of Experimental Medicine. 2016,213(7):1267-1284. PubMed ID: 27242167
   
   

   Authors in this article generated an SLC33A1 Tg mouse model, which can selectively overexpress human SLC33A1 in neurons. Through the model the authors find that the activity of SLC33A1 can regulate the acetyl-CoA flux. Besides, the increased expression of SLC33A1 can affect key neuronal metabolic pathways, thus causing an autistic-like phenotype.

2. Pehar M., et al. SLC33A1/AT-1 regulates the induction of autophagy down-stream of IRE1/XBP1. Journal of Biological Chemistry. 2012. PubMed ID: 22787145
   
   

   Authors in this article focus on the unfolded protein response (UPR) and autophagy/ERAD(II). And SLC33A1 regulates the influx of acetyl-CoA into the endoplasmic reticulum (ER) lumen. At last, they find that IRE1/XBP1 controls the induction of autophagy by regulating Atg9A acetylation and AT-1 expression levels.

3. Lin P., et al. A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). American Journal of Human Genetics. 2008, 83(6):752-759. PubMed ID: 19061983
   
   

   This article reveals that a mutation of SLC33A1 is related to the autosomal-dominant spastic paraplegia (SPG42), a neurodegenerative disorder. The passage suggests a critical role of SLC33A1/AT-1 in motor-neuron development and function.

4. Liu P., et al. S113R mutation in SLC33A1 leads to neurodegeneration and augmented BMP signaling in a mouse model. Disease Models & Mechanisms. 2017, 10(1):53-62. PubMed ID: 27935820
   
   

   This article focuses on a mutation of SLC33A1, the S113R mutation (c.339T>G) which previously has been found in individuals with hereditary spastic paraplegia type 42 (SPG42). The passage finally reveals that SLC33A1 can negatively regulate BMP signaling in mice.

5. Kanamori A., et al. Expression Cloning and Characterization of a cDNA Encoding a Novel Membrane Protein Required for the Formation of O-Acetylated Ganglioside: A Putative Acetyl-CoA Transporter. Proceedings of the National Academy of Sciences of the United States of America. 1997, 94(7): 2897. PubMed ID: 9096318
   
   

   Authors of this article isolated a cDNA, AT-1 (also named SLC33A1). The gene encodes a novel protein, SLC33A1. The authors also explore their function and expression. SLC33A1 may be an acetyl-CoA transporter necessary for O-acetylation of gangliosides.

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Reference

1. Pehar M., et al. (2012). Slc33a1/at-1 regulates the induction of autophagy down-stream of ire1/xbp1. Journal of Biological Chemistry.

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