Typically proteins are co-translationally translocated into the ER, although some are post-translationally translocated. So typical is this mechanism for protein export, it has attained the status of being the ‘conventional’ pathway when compared to the secretion of a handful of proteins that utilise alternative ‘non-conventional’ routes of cellular exit. The endoplasmic reticulum (ER) and Golgi apparatus together form the endo-membrane system responsible for the targeting of the vast majority of proteins to the extracellular space and to specialised sub-cellular compartments. Here, we attempt to summarise these observations and to provide a rationale for the existence of the multiple mechanisms proposed.
These of course may not be mutually exclusive, but may each make a specific contribution to IL-1β-dependent inflammation. Multiple observations and proposals have been made that do not allow the formation of a single unified mechanism of secretion, but rather suggest that there are multiple mechanisms. However, how IL-1β is secreted from the cell is not clear. Following caspase-1-dependent processing of pro-IL-1β, mature IL-1β is rapidly secreted from the cell.
Likewise, pro-caspase-1 is recruited to ASC via a homotypic interaction of CARD domains facilitating caspase-1 activation. The PYD domain of NLRP3 recruits the adaptor molecule apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) via a homotypic interaction with its PYD domain. NLRP3 has a tripartite structure with a PAMP/DAMP sensing C-terminal leucine rich repeat (LRR), a central nucleotide binding (or NACHT) domain and an N-terminal pyrin domain (PYD). The best characterised inflammasome, is formed by the cytosolic PRR NLRP3. 1A) a molecular scaffold composed of adaptor molecules, a cytosolic pattern recognition receptor, and pro-caspase-1. The activation of caspase-1 occurs via recruitment to a multi-protein complex termed the inflammasome ( Fig. Pro-IL-1β is cleaved by the pro-inflammatory protease caspase-1. The primed cell must now encounter a further PAMP, or DAMP (danger associated molecular pattern, endogenous molecules released from dead cells) to induce the processing and secretion of an active IL-1β molecule. Induction of pro-IL-1β expression is generally referred to as a priming step, and is an inefficient secretion stimulus. PAMPs act through pattern recognition receptors (PRR's) on macrophages to regulate pathways that control gene expression. It is produced as an inactive 31 kDa precursor, termed pro-IL-1β, in response to molecular motifs carried by pathogens called ‘pathogen associated molecular patterns’ (PAMPs). It is produced and secreted by a variety of cell types although the vast majority of studies have focussed on its production within cells of the innate immune system, such as monocytes and macrophages. It is also the best characterised and most studied of the 11 IL-1 family members. Interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine that is crucial for host-defence responses to infection and injury.
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