Expanding Proteostasis by Membrane Trafficking Networks

Abstract

The folding biology common to all three kingdoms of life (Archaea, Bacteria, and Eukarya) is proteostasis. The proteostasis network (PN) functions as a "cloud" to generate, protect, and degrade the proteome. Whereas microbes (Bacteria, Archaea) have a single compartment, Eukarya have numerous subcellular compartments. We examine evidence that Eukarya compartments use coat, tether, and fusion (CTF) membrane trafficking components to form an evolutionarily advanced arm of the PN that we refer to as the "trafficking PN" (TPN). We suggest that the TPN builds compartments by generating a mosaic of integrated cargo-specific trafficking signatures (TRaCKS). TRaCKS control the temporal and spatial features of protein-folding biology based on the Anfinsen principle that the local environment plays a critical role in managing protein structure. TPN-generated endomembrane compartments apply a "quinary" level of structural control to modify the secondary, tertiary, and quaternary structures defined by the primary polypeptide-chain sequence. The development of Anfinsen compartments provides a unifying foundation for understanding the purpose of endomembrane biology and its capacity to drive extant Eukarya function and diversity.

Cargo Capture and Bulk Flow in the Early Secretory Pathway

“…This is part of an intricate, carefully balanced system termed proteostasis that involves hundreds of cellular factors (Hutt & Balch 2013). For individual proteins, the final outcome depends on the thermodynamic stability of folded and incompletely folded forms and on the kinetics by which various conformational states are reached, maintained, and lost within the ER proteostasis environment (Kowalski et al 1998, Wiseman et al 2007.…”

“…Where do we stand today? For some influential reviews from different periods in this ongoing debate, see Bonifacino & Glick (2004), Borgese (2016), Geva & Schuldiner (2014), Hauri et al (2000), Herrmann et al (1999), Hurtley & Helenius (1989), Hutt & Balch (2013), Lee et al (2004), Lippincott-Schwartz et al (2000), Mayor & Riezman (2004), Palade (1975), Pelham (1994), Pfeffer & Rothman (1987), Warren & Mellman (1999), and Zanetti et al (2012).…”

Malfolded Protein Structure and Proteostasis in Lung Diseases

“…In the first stage, protein synthesis is regulated at the level of transcription, RNA stability, and translation. In the second and less well-studied stage, proteostasis mechanisms are required for protein folding, processing, trafficking, and degradation (5,7,8). Unless this second stage is successful, the protein will not be available in sufficient quantities or will be improperly folded, potentially affecting its function or localization within the cell.…”

Hallmarks of therapeutic management of the cystic fibrosis functional landscape

“…Proteostasis is built on ancient and conserved rules that emphasize that there is no such thing as a ‘wild-type’ sequence, but rather a collection of evolving variants that must be continuously managed to optimize function for survival and fitness 18 . From an evolutionary perspective, proteostasis pathways have been considerably amplified and specialized to facilitate the expanding complexity of the protein fold found in higher eukaryotes, particularly in response to compartmentalization 4,18,47–50 , and therefore represent an unparalleled opportunity to ‘use biology to fix biology’, much as the immune system adapts to evolving pathogen challenges, such as Pseudomonas species invasion in the lung, to optimize its defensive function.…”