This pathogen that is more virulent than the enteropathogenic strains and exhibits an extremely efficient growth in lymph nodes during late phases of infection is also equipped with an antiphagocytic capsule, which likely contributes. Taken together, based on our data, we suggest a hypothetical model of this YopK-RACK1 interplay that would account for the ability of Yersinia to cause an instant phagocytic block. In this model, antiphagocytosis involves action at a distance from the bacterial surface where YopK ensures specific spatial delivery of antiphagocytic effectors using RACK1 as a marker for an active phagocytic signaling machinery. Multiple homeostatic mechanisms that control protein folding and assembly and promote the disposal of defective proteins operate in distinct cellular compartments to afford protection from endogenous proteotoxic stress. The endoplasmic reticulum is the folding and assembly site for resident structural proteins and enzymes, as well as for secretory and plasma Oxysophocarpine membrane proteins. This remarkable workload is managed by efficient and high-fidelity protein folding and misfold-correction systems, based on ATP-dependent chaperones and disulfide isomerases, in parallel with quality control mechanisms that allow Golgi transit only to properly folded proteins. Furthermore, clearance of aberrant proteins retained in the ER is mediated through the ERassociated degradation pathway, a multi-step process which requires recognition of defective proteins, retro-translocation to the cytosolic side of the ER membrane, ubiquitination and degradation by the 26S proteasome. Nonetheless, the cellular protein-folding Orbifloxacin capacity and the ERAD pathway may be impaired and/or overloaded by a variety of pathological conditions that perturb energy and calcium homeostasis, increase secretory protein synthesis and/or interfere with protein glycosylation and disulfide bond formation. In such cases the intralumenal accumulation of unfolded/malfolded proteins determines ER stress, which in turn activates a complex cascade of survival signaling pathways, collectively termed unfolded protein response. This aims at relieving ER stress by attenuating the rate of protein synthesis and by up-regulating the protein folding enzymes, the ERAD machinery and the secretory capacity. If homeostasis cannot be restored, UPR-activated machineries can trigger death/senescence programs. It is increasingly evident that the UPR has a major role in cancer, where it is required to maintain the malignant phenotype and to develop resistance to chemotherapy. In fact cancer cells must adapt to nutrient starvation and hypoxia, which affect cellular redox status and availability of energy from ATP hydrolysis. This is expected to compromise their protein folding capacities, predisposing to ER stress. Hence, upregulation of the ERAD-UPR pathways may substantially contribute to the complex cellular adaptations needed for cancer progression. In this regard it is known that many ERresident proteins are deregulated, post-translationally modified, abnormally secreted and/or cell surface re-localized in various cancer types. The multifaceted ERAD gene SEL1L encodes for at least three different protein isoforms, i.e., the canonical ER-resident SEL1LA, a cargo receptor that associates with the E3 ubiquitin-protein ligase HRD1, and the smaller, recently cloned SEL1LB and -C, that lack the Cterminal SEL1LA membrane-spanning region for insertion into the ER. Several reports have demonstrated that SEL1L protein expression varies in human tumors relative to matched normal tissues, suggesting an involvement in cancer progression. We report here the identification, characterization and subcellular localizations of two novel anchorless endogenous SEL1L variants, p38 and p28, studied in the breast cancer cell lines SKBr3 and MCF7, the multiple myeloma line KMS11 and the non-tumorigenic lines MCF10A and 293FT. We found that: i. p38 and p28 are encoded by the 59 end of the SEL1L gene; ii. p38 is up-regulated and constitutively secreted in the cancer cells, differently from the non-tumorigenic MCF10A line.