Moving the Cellular Peptidome by Transporters

Abstract

Living matter is defined by metastability, implying a tightly balanced synthesis and turnover of cellular components. The first step of eukaryotic protein degradation via the ubiquitin-proteasome system (UPS) leads to peptides, which are subsequently degraded to single amino acids by an armada of proteases. A small fraction of peptides, however, escapes further cytosolic destruction and is transported by ATP-binding cassette (ABC) transporters into the endoplasmic reticulum (ER) and lysosomes. The ER-resident heterodimeric transporter associated with antigen processing (TAP) is a crucial component in adaptive immunity for the transport and loading of peptides onto major histocompatibility complex class I (MHC I) molecules. Although the function of the lysosomal resident homodimeric TAPL-like (TAPL) remains, until today, only loosely defined, an involvement in immune defense is anticipated since it is highly expressed in dendritic cells and macrophages. Here, we compare the gene organization and the function of single domains of both peptide transporters. We highlight the structural organization, the modes of substrate binding and translocation as well as physiological functions of both organellar transporters.

The tumor microenvironment in renal cell cancer

“…The response to immune checkpoint inhibitors has been shown to correlate with the mutational burden of the tumor cell [10,11] and the number of mutations in a typical ccRCC is several orders of magnitude less than that observed in melanoma or NSCLC [12], suggesting that ccRCC should have limited expression of novel tumor-specific antigens and at best, a modest immune cell infiltrate. The molecular basis for the robust immune cell infiltration and response to immunotherapy observed with RCC is not entirely clear but may be due to the upregulation of genes associated with antigen processing and peptide loading onto HLA Class I molecules such as TAP1 and TAP2 [13] or antigen presentation such as HLA-A, B, and C, and β 2 -microglobulin. Senbabaoglu et al recently compared the expression of these genes in various tumors with that of adjoining normal tissue and observed the greatest variance between the paired tissues in ccRCC tumors [4].…”

Insights into AMS/PCAT transporters from biochemical and structural characterization of a double Glycine motif protease

“…The translocation of peptides and proteins across the membrane bilayer is a fundamental process in all three domains of life (Rapoport et al, 2017). Bacteria secrete peptides and proteins for survival and adaptation to different ecological niches, to mediate intercellular signaling, and to deter or kill other microorganisms that may compete for limited resources (Abele and Tampé, 2018). Transport of intracellularly produced peptides in bacteria is mediated by ABC transporters, which utilize the energy of ATP binding and hydrolysis to translocate substrates across the bilayer (ter Beek et al, 2014; Beis, 2015).…”

Salicylic acid influences the protease activity and posttranslation modifications of the secreted peptides in the moss Physcomitrella patens

“…Peptides from such proteins might be exported into the apoplast during fusion of vacuolar vesicles with the plasma membrane. Also, peptides can be transported into the extracellular space by peptide transporters …”