The ceramide transporter and the Goodpasture antigen binding protein: one protein – one function?

Abstract

The Goodpasture antigen-binding protein (GPBP) and its splice variant the ceramide transporter (CERT) are multifunctional proteins that have been found to play important roles in brain development and biology. However, the function of GPBP and CERT is controversial because of their involvement in two apparently unrelated research fields: GPBP was initially isolated as a protein associated with collagen IV in patients with the autoimmune disease Goodpasture syndrome. Subsequently, a splice variant lacking a serine-rich domain of 26 amino acids (GPBPD26) was found to mediate the cytosolic transport of ceramide and was therefore (re)named CERT. The two splice forms likely carry out different functions in specific sub-cellular localizations. Selective GPBP knockdown induces extensive apoptosis and tissue loss in the brain of zebrafish. GPBP/GPBPD26 knockout mice die as a result of structural and functional defects in endoplasmic reticulum and mitochondria. Because both mitochondria and ceramide play an important role in many biological events that regulate neuronal differentiation, cellular senescence, proliferation and cell death, we propose that GPBP and CERT are pivotal in neurodegenerative processes. In this review, we discuss the current state of knowledge on GPBP and CERT, including the molecular and biochemical characterization of GPBP in the field of autoimmunity as well as the fundamental research on CERT in ceramide transport, biosynthesis, localization, metabolism and cell homeostasis. Keywords: autoimmunity, ceramide, GPBP/CERT, neurodegenerative diseases. J. Neurochem. (2010) 113, 1369-1386. | 2010 | 113 | 1369-1386 doi: 10.1111/j.1471-4159.2010 (Raya et al. 1999). Goodpasture's syndrome is a strictly human disorder caused by antibodies directed against the non-collagenous domain of the a3-chain of collagen type IV [a3 (IV) NCI]. Collagen is a major component of the extracellular matrix. The autoantibodies cause rapid functional disruption of the basement membrane of lungs, kidneys and the choroid plexus (Salama et al. 2001). GPBP is a soluble extracellular protein which binds and phosphorylates the antigen in this syndrome. Its expression is increased in other spontaneous autoimmune disorders including Goodpasture's syndrome, lupus erythematosus, pemphigoid and lichen planus (Raya et al. 2000), suggesting that GPBP might be an important protein in autoimmune disorders, where autoantigens arise from abnormal protein domain organization. JOURNAL OF NEUROCHEMISTRYSubsequently, in 2003, Hanada and colleagues showed that a spliced variant of GPBP which lacks a serine-rich domain composed of 26 aa residues was responsible for the cytosolic trafficking of ceramide from the endoplasmic reticulum (ER), to the Golgi apparatus. Hence, this isoform was termed as CERT (Hanada et al. 2003). Since the longer isoform also has ceramide transport properties in vitro, GPBP was renamed as CERT L (Hanada et al. 2003).Thus far it is not clear how the extracellular function of GPBP/CERT L , which is related to immu...

Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

“…Because the collection of blood is noninvasive and more acceptable and feasible for serial measures, we initially focused on the characterization of ceramides and metabolites in this medium. Lastly, ceramides are hydrophobic, so they are carried on lipoproteins in the blood, with the greatest concentrations in VLDL and LDL (Hammad et al ., 2010) and the ceramide transporter (CERT) (Mencarelli et al ., 2010). The composition and quantification of the specific acyl chain lengths of ceramides and DHCer on lipoproteins or CERT may differ by age and with disease onset.…”

The involvement of the ceramide transporter in Alzheimer’s disease Investigating the binding properties of the ceramide transporter in the human brain by optimizing the splitubiquitin Yeast Two-Hybrid system

“…The ceramide transporter long isoform (CERT L ) is also known as the Goodpasture antigenbinding protein (GPBP), which was discovered in the Goodpasture's syndrome. The GPBP/CERT L protein consist of three functional domains the plechstrin homology domain, the middle region (MR) and the steroidogenic acute regulatory protein-related lipid transfer region (6). Since the MR domain is responsible for the binding of CERT L with other proteins, it was decided to use this part as bait.…”

The mammalian START domain protein family in lipid transport in health and disease

“…Within this subfamily, STARD2/PCTP and STARD11/ CERT have been studied in more detail and have been recently reviewed by others (Kanno et al 2007a,b, Hanada et al 2009, Kang et al 2010, Mencarelli et al 2010. Therefore, only summaries of the recent data on the members of this subfamily are provided.…”