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, 50 (6), 477-88

A Bacterial Toxin and a Nonenveloped Virus Hijack ER-to-cytosol Membrane Translocation Pathways to Cause Disease


A Bacterial Toxin and a Nonenveloped Virus Hijack ER-to-cytosol Membrane Translocation Pathways to Cause Disease

Kaiyu He et al. Crit Rev Biochem Mol Biol.


A dedicated network of cellular factors ensures that proteins translocated into the endoplasmic reticulum (ER) are folded correctly before they exit this compartment en route to other cellular destinations or for secretion. When proteins misfold, selective ER-resident enzymes and chaperones are recruited to rectify the protein-misfolding problem in order to maintain cellular proteostasis. However, when a protein becomes terminally misfolded, it is ejected into the cytosol and degraded by the proteasome via a pathway called ER-associated degradation (ERAD). Strikingly, toxins and viruses can hijack elements of the ERAD pathway to access the host cytosol and cause infection. This review focuses on emerging data illuminating the molecular mechanisms by which these toxic agents co-opt the ER-to-cytosol translocation process to cause disease.

Keywords: Bacterial toxin; chaperone; cholera toxin; endoplasmic reticulum-associated degradation; infection; membrane transport; polyomavirus; ubiquitin-proteasome system.

Conflict of interest statement

Declaration of interest: None of the authors have a conflict of interest.


Figure 1
Figure 1. ER-associated degradation
A. ER-to-cytosol transport of misfolded protein. ERAD can be broadly divided into three distinct steps. Step 1: ER lumenal factors recognize and target the misfolded substrate to the ERAD membrane complex. Step 2: The substrate is physically transported across the ER membrane by traversing a retro-translocon to reach the cytosol where it is ubiquitinated. Step 3: Specific cytosolic factors anchored to the retro-translocon engage the ubiquitinated substrate, ejecting it into the cytosol which is then delivered to the proteasome for degradation. B. ER-to-cytosol transport of foreign agents. Foreign agents such as a bacterial toxin (cholera toxin) and a virus (SV40) can hijack the existing ER-to-cytosol gateway to access the cytosol during infection.
Figure 2
Figure 2. Cholera toxin co-opts the ERAD machinery to retro-translocate into the cytosol
A. Structure of cholera toxin. The holotoxin consists of a toxic A (CTA) subunit associated with the receptor-binding B homo-pentameric (CTB) subunit. B. Cholera toxin intoxication pathway. CT intoxicates cells by binding to host surface GM1 receptor, which delivers the holotoxin to the ER by retrograde transport (step i). In the ER, CTA's disulfide bond is reduced (step ii) to liberate the toxic CTA1 chain (step iii). By disguising as a misfolded protein, CTA1 hijacks ERAD machinery and reaches the cytosol (step iv), where it triggers a host-signaling cascade (step v) to activate the chloride channel to cause disease (step vi). C. Detailed overview of CT ER-to-cytosol transport. Step 1: Once in the ER, CT is captured by BiP when the J-protein ERdj5 stimulates BiP's ATPase activity. This reaction occurs proximal to the ERAD machinery because ERdj5 is anchored to the ER membrane by Sel1L. Step 2: To release toxin from BiP, ER-resident NEFs (Grp170 and/or Sil1) induces nucleotide exchange of BiP, converting BiP from a high to low substrate-binding affinity state. Step 3: Upon release, CTA is subsequently handed off to the redox chaperones (PDI-Ero1), which unfold the toxin to prime it for retro-translocation. Step 4: Unfolded CTA1 is delivered to Derlin-1 that is part of the proposed Hrd1 membrane translocon complex. Step 5: The toxin navigates through the retro-translocon in a process regulated by the ubiquitin ligase activity of Hrd1 and the cytosolic deubiquitinase activity of YOD1. Step 6: Upon arrival at the cytosol, CTA1 refolds to an active conformation, triggering a downstream signaling pathway that causes disease.
Figure 3
Figure 3. The non-enveloped virus SV40 co-opts elements of the ERAD machinery to translocate into the cytosol
A. Structure of SV40. SV40 consists of 72 homo-pentamers formed by the coat proteins VP1, with each pentamer encasing either a VP2 or VP3 internal protein (see cross-section). Within this proteinaceous shell, the viral circular double-stranded DNA genome is enclosed. B. SV40 infection pathway. To infect cells, the virus recognizes the host surface glycolipid (GM1) receptor. The virus-receptor complex undergoes endocytosis (step i) to reach the ER (step ii). In the ER lumen, several ER-resident factors isomerizes/reduces the virus disulfide bonds to generate conformationally-altered hydrophobic particles (step iii). These viral particles penetrate the ER membrane to reach cytosol with the aid of several ER-membrane and cytosolic factors (step iv). During cytosolic extraction, the virus is simultaneously disassembled (step v) to prepare a subviral intermediate (containing the genome) for transport into the nucleus for infection. C. Detailed overview of SV40 ER-to-cytosol transport. Step 1: Once SV40 reaches the ER lumen, ER-resident PDI family members including ERp57, ERdj5, and PDI act on the viral particle to trigger critical conformation changes. These structural rearrangements expose the internal proteins VP2 and VP3, generating a hydrophobic viral particle. Step 2: The hydrophobic viral particle recruits BiP via the action of the J-protein ERdj3. Step 3: The NEF Grp170 induces BiP release from SV40 proximal to the ER membrane. Step 4: The hydrophobic viral particle initiates membrane penetration by interacting with and integrating into the ER membrane via engaging the membrane protein BAP31. Step 5: BAP31 in turn recruits other membrane proteins (including the ER membrane J-proteins) to the vicinity to assemble a dense platform within the ER membrane (called foci, black dots) essential for membrane penetration. Step 6: At the cytosolic interface, several cytosolic factors (including Hsc70, SGTA, and Hsp105) anchored to the ER membrane engage the viral particle, extracting it into the cytosol in an energy dependent manner. Step 7: During cytosolic extraction, the virus is simultaneously disassembled to prepare for its journey into the nucleus.

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