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Lysosomal Vitamin B12 Trafficking
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Sean Froese, Matthias R. Baumgartner
The final production of the Cbl cofactor forms requires successful export of Cbl from the lysosome into the cytosol, but the exact mechanism through which this takes place is poorly understood. Based on genetic and experimental evidence, this export requires the concerted actions of two integral membrane proteins – ABCD4 and LMBD1. Cells from patients with inherited mutations in either ABCD4 (Coelho et al., 2012) (which encodes ABCD4) or LMBRD1 (Rutsch et al., 2009) (which encodes LMBD1) have been shown to accumulate free Cbl in their lysosomes (Coelho et al., 2012; Watkins and Rosenblatt, 1986), resulting in combined deficiency of methionine synthase and methylmalonyl-CoA mutase due to an inability to produce both the methyl-Cbl and adenosyl-Cbl cofactor forms. Although the explicit contribution to lysosomal Cbl export by both proteins has yet to be elucidated, it is tempting to rationalize their functions by comparison with their protein family members. LMBD1 (lipocalin membrane receptor domain containing protein 1) is so named due to its resemblance to the lipocalin membrane receptor (LIMR), which binds and internalizes lipocalins – small secreted proteins which bind protoporphin IX among other ligands (Dufour et al., 1990). With this in mind, a receptor–transporter role has been suggested for LMBD1 in Cbl transport (Rutsch et al., 2009). ABCD4 by contrast, is part of the ATP-binding cassette transporter subfamily D, whose closest members (ABCD1–3) are all located on peroxisomal membranes and function as importers (Contreras et al., 1994; Kamijo et al., 1990; Lombard-Platet et al., 1996; Mosser et al., 1994). This is suggestive of a direct transport function of Cbl for ABCD4. Unlike the other ABCD family members, ABCD4 lacks the N-terminal peroxisomal targeting motif (Lee et al., 2014) and is therefore not sorted towards the peroxisome. Singly over-expressed ABCD4 has been found in the endoplasmic reticulum (ER) (Kashiwayama et al., 2009) and autophagosomes (Fettelschoss et al., 2017), suggesting retention and degradation of mis-targeted or poorly folded protein. ABCD4 over-expressed in the presence of LMBD1, however, has been found to correctly localize to the lysosome (Fettelschoss et al., 2017; Kawaguchi et al., 2016), suggesting a targeting/chaperoning role of LMBD1 for ABCD4. This role is further supported by the fact that LMBD1 is heavily glycosylated (Rutsch et al., 2009), while ABCD4 appears not to be (Kashiwayama et al., 2009). Thus, the protective role of LMBD1 for ABCD4 may extend to their roles within the lysosome, as well as in transit. Although these putative roles have yet to be confirmed, the above data strongly suggests that ABCD4 and LMBD1 must physically interact to successfully carry out their physiological functions. This interaction has been shown in live cells (Fettelschoss et al., 2017) using a protocol detailed later in this chapter.
ABC transporters in breast cancer: their roles in multidrug resistance and beyond
Published in Journal of Drug Targeting, 2022
Anupama Modi, Dipayan Roy, Shailja Sharma, Jeewan Ram Vishnoi, Puneet Pareek, Poonam Elhence, Praveen Sharma, Purvi Purohit
ABC transporters can carry out both influx (moving substrates into cells) and efflux (moving substrates out of cells) functions. They are involved in the transport of inorganic anions, peptides and amino acids, sugars, hydrophobic compounds and metabolites across both the plasma membrane and intracellular membranes. Among the known ABC transporters, the ABCA subfamily is primarily involved in lipid trafficking in various organs and cell types [13]. While ABCA1 and ABCA7 take part in cholesterol efflux, ABCA3 and ABCA6 are implicated in MDR [14]. The ABCD subfamily of transporters is localised to peroxisomes (ABCD1-3) and lysosomes (ABCD4) [15]. The peroxisomal transporters help with the influx of long and very long-chain fatty acids and branched-chain acyl-CoA into peroxisomes. ABCD4 helps transport vitamin B12 out of lysosomes into the cytosol [15]. Other ABC transporters that are widely reported in the literature include ABCB subfamily member 1 (ABCB1, also known as multidrug resistance protein 1/MDR1/Permeability glycoprotein/P-glycoprotein/P-gp), ABCG subfamily member 2 (ABCG2, also known as breast cancer resistance protein/BCRP), and ABC subfamily C member 1 (ABCC1, also known as MDR-associated protein 1/MRP1) [16]. These efflux pumps are expressed in many human cancers including BC and are likely responsible for drug resistance. Although the clinical trials targeting ABCB1 have not yielded success, ABC transporters’ role in the development, progression and metastatic process surpass their functionalities in drug efflux [16].