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Review
, 537 (7620), 328-38

Proteome Complexity and the Forces That Drive Proteome Imbalance

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Review

Proteome Complexity and the Forces That Drive Proteome Imbalance

J Wade Harper et al. Nature.

Abstract

The cellular proteome is a complex microcosm of structural and regulatory networks that requires continuous surveillance and modification to meet the dynamic needs of the cell. It is therefore crucial that the protein flux of the cell remains in balance to ensure proper cell function. Genetic alterations that range from chromosome imbalance to oncogene activation can affect the speed, fidelity and capacity of protein biogenesis and degradation systems, which often results in proteome imbalance. An improved understanding of the causes and consequences of proteome imbalance is helping to reveal how these systems can be targeted to treat diseases such as cancer.

Figures

Figure 1
Figure 1. An overview of proteome complexity
a, Numerous factors contribute to the generation of complex proteomes. These include (clockwise from top left): alternative splicing; the assembly of protein complexes with varied compositions; the subcellular location of proteins; the attachment of various modifications to proteins; the use of alternative upstream open reading frames (uORFs, purple) in mRNA translation; and the efficiency of mRNA translation. b, In a balanced proteome (green), the level of protein production does not exceed the capacity of protein depletion systems. To achieve this equilibrium, many factors contribute to the generation or degradation of proteins. Cellular events and states such as chromosome imbalance, oncogenic activation and errors in translation alter the proteome in ways that promote proteotoxic stress and lead to imbalance in the proteome (red). This can be buffered by an enhanced capacity for protein degradation or be exacerbated by the depletion of factors that facilitate protein folding or degradation. P, phosphate; Ub, ubiquitin.
Figure 2
Figure 2. Mechanisms that contribute to proteome imbalance and transcriptional responses
a, Genetic alterations in human cancers can generate proteome imbalance. Myc protein promotes the RNA polymerase (RNA pol) I- and RNA pol III-dependent transcription of rRNAs; it also promotes the RNA pol II-dependent transcription of ribosomal proteins to induce ribosome production. Elevated levels of some ribosomal proteins in excess of the assembled ribosome can lead to the activation of the ribosomal surveillance pathway, which stimulates cell death pathways. At the same time, Myc activates about 15% of protein-coding genes that are transcribed by RNA pol II, thereby increasing the protein-synthesis load of the cell. This is likely to increase the number of defective translation products, which lead to an increase in proteotoxic stress. Similarly, the activation of receptor tyrosine kinases (RTKs) and the PI3K signalling pathways that stimulate AKT1 and mTORC1 activity, or the overexpression of translation initiation factors eIF4F and eIF3 can increase protein synthesis, also leading to increased levels of proteotoxic stress. b, Two transcriptional response systems sense imbalance in the proteome and can elevate the cell’s capacity for protein folding or degradation. One mode of control involves the conversion of a pool of inactive HSF proteins in response to perturbations such as heat shock into an active nuclear transcription complex that binds a promoter known as a heat-shock element (HSE). This leads to the expression of heat-shock proteins (HSPs), including chaperones, and increases the cell’s capacity for protein folding. Another mode of control is the production of proteasome subunits to increase the cellular capacity for protein degradation. Under basal conditions, transcription factor NRF1 in the endoplasmic reticulum (ER) is targeted for p97-dependent proteasomal degradation through ER-associated degradation (ERAD) (not shown). However, when the activity of the proteasome is inhibited or depleted, retrotranslocated NRF1 is cleaved by an unknown protease, which facilitates the translocation of NRF1 into the nucleus where it activates the transcription of proteasome subunit genes. Global environmental and integrated stress-response pathways also attempt to rebalance the proteome through reduced translational output (red box) and enhanced cellular defence systems (green box) such as protein folding and degradation machineries. ARE, antioxidant response element; MAF, transcription factor MAF.
Figure 3
Figure 3. Regulating the stoichiometry of protein complexes
a, In proportional synthesis, the abundance and translation rates of mRNA are tuned to produce the appropriate stoichiometry for the formation of multiprotein complexes with the subunits A, B and C. b, In imbalanced synthesis, subunit A is expressed at a higher rate than subunits B and C (top), either as a result of increased transcription and translation via gene dosage effects or oncogene activation, or through genetic programming. Excess subunit A is then degraded by the ubiquitin–proteasome system. N-terminal acetylation (blue circle) through the N-acetyltransferase (NAT) system (bottom) is also proposed as a mechanism by which supernumerary subunits are marked for degradation. After the N-acetylated protein is assembled into a complex, the N-terminal acetyl residue (Ac–N degron) can no longer be recognised by the E3 ligase Doa10 due to steric blockage, and the protein is not degraded. Folded N-acetylated proteins that have not been incorporated into complexes are detected by Doa10 and marked for degradation, and misfolded proteins that contain Ac–N degrons are degraded with assistance from chaperone proteins.
Figure 4
Figure 4. Therapeutic strategies that target proteome maintenance
a, The ability of cells to respond to fluctuations in proteome balance is dictated by the cellular ratio of quality control capacity to substrate abundance. When the capacity to load ratio (y axis) is high, levels of proteotoxic stress (x axis) are low. Tumour cells may adapt to increase their quality control capacity, which enables them to become more resistant to the effects of proteotoxic stress (left). Pharmacological targeting of the pathways that regulate the balance of the proteome with drugs that inhibit chaperones or the proteasome can alter the cell’s capacity to load ratio in favour of enhanced cell death at lower levels of proteotoxic stress (right). b, A number of pathways that regulate proteome balance have been targeted using small molecules. In the nucleus, inhibitors of RNA pol I, such as CX-5461, block the production of rRNA. This isolated reduction of rRNA leads to an excess of ribosomal proteins RPL11 and RPL5, which induces p53 stabilization through inhibition of the ubiquitin ligase Mdm2. In the cytoplasm, translational control mechanisms, protein chaperones such as HSP90 and the AAA-ATPase p97 control a network of interactions that regulate the production and turnover of the defective products of translation at the ribosome. The excess of ribosomal proteins such as RPL11 and RPL5 is also increased in the context of Myc overexpression, which promotes the production of ribosomal proteins. Several small-molecule inhibitors, including the HSP90 inhibitor tanespimycin (17-AAG), the PI3K and mTOR inhibitor NVP-BEZ235 and various elongation factor 4E (EIF4E) inhibitors (4EI-1 related molecules and the natural product pateamine A), have been developed to target distinct steps in the pathway. p97 also controls the proteasomal turnover of proteins through the ERAD pathway, which might be important for determining the clinical activity of p97 inhibitor CB-5083. Ub, ubiquitin.

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