Highly sophisticated mechanisms that modulate protein structure and function, which involve synthesis and degradation, have evolved to maintain cellular homeostasis. Perturbations in these mechanisms can lead to protein dysfunction as well as deleterious cell processes. Therefore in recent years the etiology of a great number of diseases has been attributed to failures in mechanisms that modulate protein structure. Interconnections among metabolic and cell signaling pathways are critical for homeostasis to converge on mechanisms associated with protein folding as well as for the preservation of the native structure of proteins. For instance, imbalances in secretory protein synthesis pathways lead to a condition known as endoplasmic reticulum (ER) stress which elicits the adaptive unfolded protein response (UPR). Therefore, taking this into consideration, a key part of this paper is developed around the protein folding phenomenon, and cellular mechanisms which support this pivotal condition. We provide an overview of chaperone protein function, UPR via, spatial compartmentalization of protein folding, proteasome role, autophagy, as well as the intertwining between these processes. Several diseases are known to have a molecular etiology in the malfunction of mechanisms responsible for protein folding and in the shielding of native structure, phenomena which ultimately lead to misfolded protein accumulation. This review centers on our current knowledge about pathways that modulate protein folding, and cell responses involved in protein homeostasis.

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The islet amyloid polypeptide (IAPP) or amylin maintains a key role in metabolism. This 37-residues-peptide could form pancreatic amyloids, which are a characteristic feature of diabetes mellitus type 2. However, some species do not form amyloid fibril structures. By employing a biomimetic approach, we generated an extensive panel of optimized sequences of IAPP, which could drastically reduce aggregation propensity. A structural and cellular characterization analysis was performed on the C-terminal domain with the highest aggregation propensity. This allowed the observation of an aggregative phenomenon dependent of the lipid environment. Evaluation of the new F23R variant demonstrated inhibition of β-sheet structure and, therefore, amyloid formation on the native C-terminal, phenomenon that was associated with functional optimization in calcium and cholesterol management coupled with the optimization of insulin secretion by beta cells. When F23R variant was evaluated in microglia cells, a model of amyloidosis, cytotoxic conditions were not registered. In addition, it was found that C-terminal sequences of IAPP could modulate cholesterol metabolism in hepatocytes through regulation of SREBP-2, apoA-1, ABCA1, and LDLR, mechanism that may represent a new function of IAPP on the metabolism of cholesterol, increasing the LDL endocytosis in hepatocytes. Optimized sequences with only one residue modification in the C-terminal core aggregation could diminish β-sheet formation and represent a novel strategy adaptable to other pharmacological targets. Our data suggest a new IAPP function associated with rearrangements on metabolism of cholesterol in hepatocytes.

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Introduction Isthmin 2 (ISM2) is a protein which expression in humans is almost specific to the placenta. There is no previous report in the literature that investigated this protein in preeclampsia or choriocarcinoma. Methods We conducted a prospective, cross-sectional study that included women with preeclampsia, gestational hypertension and normotensive pregnancy. We measured serum concentrations of ISM2 protein and performed immunohistochemistry in placenta tissues. We also performed immunohistochemistry of ISM2 in samples from choriocarcinoma and compare with lung, prostate, colon, gastric and breast cancers. Results A total of 81 patients were included, 30 with preeclampsia, 21 with gestational hypertension and 30 controls. The ISM2 protein was found to be decreased in patients with preeclampsia compared to the control group (P = 0.036). These results were confirmed by immunohistochemistry. We also found that ISM2 protein was overexpressed in choriocarcinoma. Discussion Taken together, our results suggest an angiogenic function for ISM2. Its serum level decreased in our patients with preeclampsia could be reflecting that it is involved in the pathogenesis of the disease; on the other hand its high expression in choriocarcinoma, indicates that ISM2 may play an active role in the angiogenesis of this and other cancers.