Quality control of protein folding in extracellular space

Abstract

The pathologies of many serious human diseases are thought to develop from the effects of intra- or extracellular aggregates of non-native proteins. Inside cells, chaperone and protease systems regulate protein folding; however, little is known about any corresponding mechanisms that operate extracellularly. The identification of these mechanisms is important for the development of new disease therapies. This review briefly discusses the consequences of protein misfolding, the intracellular mechanisms that control folding and the potential corresponding extracellular control processes. Finally, a new speculative model is described, which proposes that newly discovered extracellular chaperones bind to exposed regions of hydrophobicity on non-native, extracellular proteins to target them for receptor-mediated endocytosis and intracellular, lysosomal degradation.

Figure 1

Schematic diagram of protein aggregation pathways. For each protein, there is thought to be an ensemble of possible structures: native (N) and non-native (NN), the latter including partly unfolded intermediates (I₁ and I₂) and unfolded (U) structures. The non-native structures are prone to associate with each other to form aggregates, although native proteins may sometimes also aggregate to form fibres. Non-fibrillar (amorphous) aggregates result from non-specific interactions between many different conformations, whereas highly structured amyloid fibrils can be formed by β-sheet-rich intermediates. Soluble structures are shown in the internal blue rectangle, insoluble structures in the outer white region.

Figure 2

Outline of main intracellular controls of protein folding. In the cytosol, non-native proteins are recognized by chaperones and are targeted for refolding or proteolytic degradation by the proteasome or lysosome (Hohfeld et al, 2001). In the endoplasmic reticulum (ER), newly synthesized proteins or other non-native proteins are assisted to fold by chaperones. ER–Golgi cycling may occur at this stage. If a native conformation is achieved, the protein may be secreted from the cell. If a non-native conformation persists, it can be proteolytically degraded within the ER, retro-translocated to the cytosol and degraded by the proteasome, or transported to the lysosome (Trombetta & Parodi, 2003). Under some circumstances, aggregated non-native proteins can accumulate as insoluble deposits inside the ER or in the cytosol as an aggresome. For simplicity, cofactors involved in many of these processes are not shown. See key for other details.

Figure 3

Speculative model for extracellular chaperone-mediated clearance of non-native proteins. Non-native (NN) extracellular proteins are bound by extracellular chaperones (ECs) that mediate their uptake into cells by receptor-mediated endocytosis. EC–NN complexes are internalized and moved by vesicular transport to lysosomes, where they are degraded. Receptors are recycled back to the cell surface (not shown). The primary sites of action of this process are likely to be the liver and the reticuloendothelial system. See key for other details.