1. Protein Quality Control in the Cytosol and the Endoplasmic Reticulum: Brothers in Arms 
Alexander Buchberger, Bernd Bukau, Thomas Sommer 
Molecular Cell 
Volume 40, Issue 2, Pages (October 2010)
DOI: /j.molcel
Copyright © 2010 Elsevier Inc. Terms and Conditions

2. Figure 1 Stress Response to Protein Damage
Protein damage actuates a dual stress response. First, damaged proteins are direct targets of quality control proteins and either repaired or eliminated, leading to a reduction of the stressor. Second, damaged proteins induce adaptive responses aimed at increasing the levels of quality control proteins and decreasing global translation, thus avoiding additional damage. Note the crosstalk between the two branches of stress response.
Molecular Cell  , DOI: ( /j.molcel )
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3. Figure 2 Damage Recognition
Depicted are quality control components recognizing various nonnative protein conformers in the cytosol and ER. Productive (re)folding pathways to the native state are not shown. In the cytosol, unfolded proteins are recognized by Hsp70 in concert with Hsp40 cochaperones. More mature folding intermediates are, additionally, recognized by Hsp90 or TRiC/CCT. sHsps ameliorate protein aggregation by loosening aggregates and facilitating aggregate solubilization, which is driven by Hsp100. In addition, certain E3 ubiquitin ligases (see box) can directly bind unfolded or damaged proteins and target them for proteasomal degradation. In the ER, the role of Hsp70, Hsp40, and Hsp90 in damage recognition is conserved, while there is no TRiC/CCT homolog, and sHsps are restricted to plants. In addition, PDIs and, in higher eukaryotes, UGGT (not shown) bind directly to nonnative proteins. The HRD E3 ubiquitin ligase complex binds through its Hrd1 and Hrd3 subunits to misfolded transmembrane and luminal ER proteins, respectively, and targets them for retrotranslocation to the cytosol and proteasomal degradation.
Molecular Cell  , DOI: ( /j.molcel )
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4. Figure 3 Pathway Selection
(A) In the cytosol of metazoans, Hsp70 substrates are ubiquitylated and thereby targeted for proteolysis by the cochaperone and E3 ubiquitin ligase CHIP. The specific fate of CHIP substrates is determined by distinct nucleotide exchange factors. BAG-1 and BAG-3 together with HspB8 mediate proteasomal and autophagic degradation, respectively. BAG-2 and HspBP1 inhibit CHIP to allow for release of nonnative substrates (U), which can partition between folding to the native state (N) and further cycles of Hsp70 interaction. In yeast, the E3 ubiquitin ligases Ubr1 and San1 mediate the proteasomal degradation of cytosolic quality control substrates in a Hsp70-dependent process. The function of Hsp70 in this pathway is not understood in mechanistic detail. Hsp110 plays an important but weakly defined role in both CHIP- and Ubr1/San1-dependent protein degradation pathways.
(B) In the ER, unfolded glycoproteins carrying Glc1Man9 glycans are bound by the lectins calnexin (CNX) and calreticulin (CRT) and can fold with the help of chaperones and PDIs (not shown). The activity of ER glucosidase II sets a time window for CNX/CRT-assisted folding. After removal of the terminal glucose residue (red), native Man9 glycoproteins are sorted for ER exit, whereas, in most eukaryotes, near-native conformers are recognized and reglucosylated by UGGT for another CNX/CRT-assisted folding cycle. Alternatively, the low, constitutive activity of ER mannosidase I (Mns1) targets nonnative conformers for further mannose trimming by EDEMs (Htm1) and ERAD.
(C) Luminal ER glycoproteins destined for ERAD require a further commitment step for retrotranslocation and degradation. Nonnative proteins bind to the HRD complex in a glycan-independent manner through interactions with Yos9, Hrd3, and BiP. Only substrates carrying Man7 glycans are specifically recognized through the MRH domain of Yos9, thereby triggering an ill-defined commitment step. Note that the exact nature of the interactions between ERAD substrates and Yos9, Hrd3, and BiP is still unknown.
Molecular Cell  , DOI: ( /j.molcel )
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5. Figure 4 Aggregate Handling
In the cytosol, aggregated proteins can be solubilized by Hsp70 and Hsp40 in concert with Hsp100 (only present in lower eukaryotes), followed by a triage decision between refolding to the native state or proteasomal degradation. As a speculative possibility, aggregated proteins already carrying ubiquitin chains may be directly solubilized through an as yet unknown mechanism and degraded. Aggregates resistant to solubilization are sorted for autophagy through the adaptor proteins p62 and NBR1, which recruit ubiquitylated cargo to LC3 for subsequent incorporation into autophagosomes. In the ER, solubilization of protein aggregates has not been demonstrated and is thus speculative. Aggregates are sequestered into the ERAC and subsequently degraded by autophagy in a mechanistically poorly understood process.
Molecular Cell  , DOI: ( /j.molcel )
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6. Figure 5 Induction of Stress Responses
HSF1 is sequestered by Hsp90, Hsp70, and Hsp40 in an inactive, monomeric state in the cytosol of unstressed cells. Damaged proteins induce the HSR by titrating chaperones away from HSF1, thus allowing HSF1 trimerization, nuclear transport, and transcriptional activation at promoters carrying HSEs. Note that the contribution of Hsp70/40 to the actual induction phase of the HSR is unclear. Ire1 exists in a monomeric, inactive, BiP-bound state in unstressed cells. Protein damage induces the oligomerization of Ire1 followed by transactivation of the cytosolic dual kinase and endoribonuclease domain. Active, transphosphorylated Ire1 catalyzes the splicing of HAC1/XBP1 pre-mRNA, allowing Hac1/XBP1 translation, nuclear transport, and transcriptional activation at promoters carrying UPREs. Whereas Ire1 oligomerization has been proposed to be triggered by direct binding of unfolded proteins to Ire1, the role of BiP sequestration in the induction of the UPR is still under debate.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2010 Elsevier Inc. Terms and Conditions