Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum.

The plant cytotoxin ricin enters target mammalian cells by receptor-mediated endocytosis and undergoes retrograde transport to the endoplasmic reticulum (ER). Here, its catalytic A chain (RTA) is reductively separated from the cell-binding B chain, and free RTA enters the cytosol where it inactivates ribosomes. Cytosolic entry requires unfolding of RTA and dislocation across the ER membrane such that it arrives in the cytosol in a vulnerable, nonnative conformation. Clearly, for such a dislocated toxin to become active, it must avoid degradation and fold to a catalytic conformation. Here, we show that, in vitro, Hsc70 prevents aggregation of heat-treated RTA, and that RTA catalytic activity is recovered after chaperone treatment. A combination of pharmacological inhibition and cochaperone expression reveals that, in vivo, cytosolic RTA is scrutinized sequentially by the Hsc70 and Hsp90 cytosolic chaperone machineries, and that its eventual fate is determined by the balance of activities of cochaperones that regulate Hsc70 and Hsp90 functions. Cytotoxic activity follows Hsc70-mediated escape of RTA from an otherwise destructive pathway facilitated by Hsp90. We demonstrate a role for cytosolic chaperones, proteins typically associated with folding nascent proteins, assembling multimolecular protein complexes and degrading cytosolic and stalled, cotranslocational clients, in a toxin triage, in which both toxin folding and degradation are initiated from chaperone-bound states.

Patient experience with intravenous biologic therapies for ankylosing spondylitis, Crohn's disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, and ulcerative colitis.

OBJECTIVE: The objective of this study was to describe patient experience with intravenous (IV) biologics for ankylosing spondylitis, Crohn's disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, or ulcerative colitis. METHODS: Semi-structured telephone interviews were conducted in 405 patients with these autoimmune diseases who were receiving an IV biologic to treat their disease. RESULTS: On a 7-point scale (1= not at all satisfied; 7= very satisfied), mean satisfaction with IV medication was rated 6.1; 77% of patients rated satisfaction as 6 or 7. The most frequently perceived benefits of IV therapy were related to supervision provided by health care professionals. Most patients (82%, n=332) preferred their IV medication to subcutaneous injection. The three most common reasons for preferring IV were not wanting to self-inject (43%), less frequent dosing (34%), and preference for administration by a health care professional (24%). African-American/black patients had a stronger preference for IV administration than Caucasian/white patients (97% vs 80%, P<0.05) and a greater dislike of needles/self-injection (71% vs 40%, P<0.05). Hospital outpatient departments were not rated as well as physician in-office infusion. Only half (49%) of the patients reported that both they and their physician equally influenced the choice to switch from subcutaneous to IV therapy, and only 30% were given a choice of infusion center. CONCLUSION: Users of IV biologics are highly satisfied with their medications and perceive the opportunity for health care provider interaction at their infusion facilities as an advantage of their regimen. These findings support continued need for IV therapeutic options and shared decision-making between patients and physicians while selecting biologic treatments.