- Unfolded protein response
The unfolded protein response (UPR) is a stress response that is critical to maintaining protein homeostasis (proteostasis)- the functional concentration of properly folded protein concentration in an organism. The UPR in entirety involves stress signals in the endoplasmic reticulum the mitochondria and the cytoplasm that are activated by increases in misfolded proteins. The increase in misfolded proteins affect protein concentration and can result in the aggregation of protein species. To restore protein homeostasis, these stress signals up-regulate or down-regulate protein transcription as well as regulate protein translation. These systems also influence protein folding by increasing the concentration of chaperones to aid in the folding process. In addition, these systems can increase the activity of the endoplasmic reticulum-associated degradation (ERAD) pathway, to deal with the increase in misfolded proteins. Eventually, sustained activation of the UPR will lead to cellular apoptosis.
- Gene expression
The production of a functional product from a given gene. Gene products can stem from protein coding or non-protein coding sequences. Non-protein coding genes include tRNAs, rRNAs, and microRNAs. The regulation of gene expression, (timing, location, and amount) is the basis for cell specification, differentiation, and morphogenesis during development and allows the animal to respond and adapt to environmental stimuli.
- Proteostasis
Proper protein function relies on a balanced system of protein synthesis, folding, trafficking and degradation to ensure a homeostatic concentration of properly processed proteins in the organism. Disruptions in any one of these events can result in alterations in the level of proteins, the accumulation of misfolded proteins, and or the aggregation of proteins. Stress responses in the cytoplasm, mitochondria, and ER keep properly folded protein concentrations in check. These systems maintain proteostasis by up-regulating or down-regulating transcriptional and translational processing of proteins or by increasing protein degradation pathways. Many disease states in humans, such as cystic fibrosis, and Alzheimer's, Parkinson's and Huntington's diseases have been attributed to the breakdown of proteostasis systems in the cell.
- Meiotic maturation
During female gamete production oocytes arrest during the diplotene stage of meiosis I before completing diakinesis and moving into meiosis II. In response to hormones, oocytes resume and complete meiosis to produce the final mature gametes. In C. elegans, meiotic maturation is triggered by major sperm protein through G-alpha-S-adenylate cyclase - protein kinase A (PKA) signaling and soma-to-germline communication.
- Unfolded protein response - Mitochondrial
Similar to the unfolded protein response in the endoplasmic reticulum, the mitochondrial UPR functions to maintain a homeostasis of the protein folding pathways. The UPR(mt) employs a mitochondria-to-nuclear signal transduction pathway, which regulates the expression of mitochondrial protective genes such as mitochondria-specific molecular chaperones and proteases. An increase in Cytochrome c Oxidase (COX) and succinate dehydrogenase (SDH) activity is an indicator of mitochondrial stress.
- Unfolded protein response - Cytosolic
A change in activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a protein that is not folded in its correct three-dimensional structure.
- Unfolded protein response - ER
Correctly folding proteins is a severely complicated process that fails at times, despite the controlled environment of the ER and numerous molecular helpers. Under normal conditions, these misfolded proteins are degraded through the ER-associated degradation (ERAD) mechanism. However, various physiological or environmental stressors can inhibit or overwhelm these normal mechanisms resulting in an increase in the amount of misfolded proteins, which trigger the Unfolded Protein Response (UPR). Organisms have evolved the UPR to handle this ER stress and suppress the toxicity of accumulated misfolded proteins (proteotoxicity). In mammals the UPR attenuates protein synthesis through PERK/PEK1 and increases transcription of folding and ERAD components through activation of potent transcription factors through IRE1 splicing of XBP1 mRNA and ER-stress cleavage of ATF-6. These events ultimately augment folding and enhance degradation capacity of the organelle. In C. elegans, the UPR also activates transcriptional regulators that reduce protein synthesis and increase the number of components necessary to deal with misfolded proteins.
- Metabolism
The chemical reactions, and regulation of these reactions, within an organism that are required for growth, reproduction, maintenance of proper cellular and organ function and structure, and response to the environment. These enzyme-catalyzed processes control all cellular functions including digestion, detoxification, protein synthesis, degradation and modification, and energy production.
- RNA processing
After transcription in the nucleus and before translation into a protein in the cytoplasm, newly transcribed RNA undergoes post-transcriptional modifications to become the mature mRNA. These modifications include the addition of a 5'cap and 3'poly A tail, and splicing out of noncoding introns. These modifications are needed for the RNA molecule to be protected against RNase activity as well as for it to be recognized by molecules that mediate translation into proteins. Splicing of the RNA is required to remove the portions of the message that are not supposed to be translated into the final protein product. In addition to intron and exon splicing of the pre-mRNA, ~70% of pre-mRNAs in C. elegans are trans-spliced to one of two different splice leader sequences, SL1 or SL2.
- ER-associated degradation
Correctly folding proteins is a severely complicated process. Within eukaryotes an optimal environment for protein folding is provided by the endoplasmic reticulum (ER). In addition, proper folding requires the activity of numerous molecular chaperones and folding enzymes. Despite the controlled environment and numerous molecular helpers, misfolded proteins do sometimes occur. ER-associated degradation (ERAD) is a normal cell function that detects and deals with these occurrences. Through the ERAD process, misfolded proteins are recognized, retrotranslocated to the cytosol, ubiquinated, and then degraded by the proteosome.