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Author(s): Eric A. J. Reits; Jan C. Vos; Monique Grommé; Jacques Neefjes The transporter associated with antigen processing (TAP) is a member of the family of ABC transporters that translocate [...]

MHC class I molecules usually present peptides derived from endogenous antigens that are bound in the endoplasmic reticulum. Loading of exogenous antigens on class I molecules, e.g., in cross-priming, sometimes occurs, but the intracellular location where interaction between the antigenic fragment and class I takes place is unclear. Here we show that measles virus F protein can be presented by class I in transporters associated with antigen processing-independent, N[H.sub.4]Cl-sensitive manner, suggesting that class I molecules are able to interact and bind antigen in acidic compartments, like class Il molecules. Studies on intracellular transport of green fluorescent protein-tagged class I molecules in living cells confirmed that a small fraction of class I molecules indeed enters classical MHC class II compartments (MIICs) and is transported in MIICs back to the plasma membrane. Fractionation studies show that class I complexes in MIICs contain peptides. The pH in MIIC (around 5.0) is such that efficient peptide exchange can occur. We thus present evidence for a pathway for class I loading that is shared with class II molecules.

Research was conducted to identify and compare substrate specificities of endoplasmic reticulum (ER)-resident chaperones using peptides as model substrates. The introduction of peptides into the lumen of microsomes was carried out via the ER-located peptide transporter (TAP). Results demonstrate that peptide translocation into microsomes through TAP can be utilized as a technique to monitor substrate selectivities of ER-resident chaperones.

The anthracycline drug doxorubicin is among the most used—and useful—chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy‐related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double‐strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA‐damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure–activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life. [ABSTRACT FROM AUTHOR]

Laboratory data increasingly suggest that Salmonella infection may contribute to colon cancer (CC) development. Here, we examined epidemiologically the potential risk of CC associated with salmonellosis in the human population. We conducted a population-based cohort study using four health registries in Denmark. Person-level demographic data of all residents were linked to laboratory-confirmed non-typhoidal salmonellosis and to CC diagnoses in 1994-2016. Hazard ratios (HRs) for CC (overall/proximal/distal) associated with reported salmonellosis were estimated using Cox proportional hazard models. Potential effects of serovar, age, sex, inflammatory bowel disease and follow-up time post-infection were also assessed. We found no increased risk of CC ≥1 year post-infection (HR 0.99; 95% confidence interval (CI) 0.88-1.13). When stratifying by serovar, there was a significantly increased risk of proximal CC ≥1 year post-infection with serovars other than Enteritidis and Typhimurium (HR 1.40; 95% CI 1.03-1.90). CC risk was significantly increased in the first year post-infection (HR 2.08; 95% CI 1.48-2.93). The association between salmonellosis and CC in the first year post-infection can be explained by increased stool testing around the time of CC diagnosis. The association between proximal CC and non-Enteritidis/non-Typhimurium serovars is unclear and warrants further investigation. Overall, this study provides epidemiological evidence that notified Salmonella infections do not contribute significantly to CC risk in the studied population. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex (MHC) class I molecule reveals peptides ranging from degraded intracellular antigens to CD8+ T cells which bind to the class I molecules with the help of MHC-encoded transporters. Such binding is associated with antigen processing TAP1 and TAP2. TAP1 and TAP2 are members of a protein family containing an ATP binding cassette.

The invariant chain (li) refers to a constant set of proteins associated with the major histocompatibility complex (MHC) class II molecules. No definitely proven functional role for li has been presented. To elucidate this problem, a mouse line containing a large deletion in the li gene, resulting in nonexpression of li, was developed. Characterization of this mouse line showed that li plays a role in the intracellular transport of MHC class II molecules. This mouse line will be useful in further analyses on the function of the invariant chain.

Proteasome subunits encoded by major histocompatibility complex (MHC) are not essential for the stable surface expression of MHC class I molecules. Nor are they required for the presentation of antigenic peptides to the cell surface from influenza virus and from an endogenously synthesized intracellular protein. This is discovered by furnishing a human cell line lacking both transporter and proteasome subunit genes with genes from a rat that encode the MHC-linked transporters.

Cytotoxic T-cells may be activated by the presentation of a specific antigen. This presentation takes place when a competent cell degrades a foreign protein into peptide fragments, which are then bound by molecules of the major histocompatibility complex (MHC). In humans, molecules of the MHC are often called HLA antigens, or human leukocyte antigen. Molecules of the MHC are then brought to the cell surface along with their peptide fragment. The 'cytotoxic' set of T-cells are only capable of recognizing an antigen when it is properly presented by a class I histocompatibility molecule. However, an unresolved question has been whether class I molecules can be expressed on the surface of cells without the presence of a peptide antigen fragment. Researchers have shown that when mouse lymphoma cells are cultured at reduced temperatures, between 19 and 33 degrees Centigrade, class I molecules not binding antigen fragments were detected on the cell surface. However, when the temperature of these cells is raised to 37 degrees, close to body temperature, the class I molecules quickly disappeared. These results suggest that the antigen fragment has a stabilizing effect on the class I molecular complex. Without this action, the complex is unstable at body temperature, and is undetected. At lower temperatures, the complex is more stable. The use of temperature to control the expression of class I molecules will likely aid in the study of these molecules and to a better understanding of their role in the immune response. (Consumer Summary produced by Reliance Medical Information, Inc.)

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.10.001 Byline: Tim Elliott (1), Jacques Neefjes (2) Abstract: The loading of peptides into the groove of MHC class I molecules prior to antigen presentation is a complex process. In this issue of Cell, show that peptide loading gets a helping hand from a resident ER enzyme called protein disulfide isomerase, a chaperone that has oxidoreductase activity. Author Affiliation: (1) Cancer Sciences Division, University of Southampton School of Medicine, Southampton SO16 6YD, UK (2) Division of Tumor Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands