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How Polyomaviruses Exploit the ERAD Machinery to Cause Infection

View Article: PubMed Central - PubMed

ABSTRACT

To infect cells, polyomavirus (PyV) traffics from the cell surface to the endoplasmic reticulum (ER) where it hijacks elements of the ER-associated degradation (ERAD) machinery to penetrate the ER membrane and reach the cytosol. From the cytosol, the virus transports to the nucleus, enabling transcription and replication of the viral genome that leads to lytic infection or cellular transformation. How PyV exploits the ERAD machinery to cross the ER membrane and access the cytosol, a decisive infection step, remains enigmatic. However, recent studies have slowly unraveled many aspects of this process. These emerging insights should advance our efforts to develop more effective therapies against PyV-induced human diseases.

No MeSH data available.


Related in: MedlinePlus

ER-associated degradation (ERAD) pathway. ERAD is an ER quality control pathway that identifies and triages misfolded ER proteins. In the first step, a misfolded protein is recognized by ER-resident chaperones, which target the misfolded client to the retro-translocation machinery on the ER membrane (step 1). Next the misfolded client is retro-translocated across the ER membrane by crossing the retro-translocation channel (step 2); a major component of this channel is the Sel1L-Hrd1 membrane complex. When the client emerges into the cytosol, it is ubiquitinated by the catalytic domain of Hrd1 that faces the cytosol, eventually resulting in polyubiquitinaton of the substrate (step 3). In the final step, the client is extracted into the cytosol by p97 (and its cofactors), and delivered to the proteasome for degradation (step 4). Sel1L: protein sel-1 homolog 1; Hrd1: E3 ubiquitin-protein ligase synoviolin; Poly(Ub)n: polyubiquitin chain; RING: Really Interesting New Gene finger domain.
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viruses-08-00242-f002: ER-associated degradation (ERAD) pathway. ERAD is an ER quality control pathway that identifies and triages misfolded ER proteins. In the first step, a misfolded protein is recognized by ER-resident chaperones, which target the misfolded client to the retro-translocation machinery on the ER membrane (step 1). Next the misfolded client is retro-translocated across the ER membrane by crossing the retro-translocation channel (step 2); a major component of this channel is the Sel1L-Hrd1 membrane complex. When the client emerges into the cytosol, it is ubiquitinated by the catalytic domain of Hrd1 that faces the cytosol, eventually resulting in polyubiquitinaton of the substrate (step 3). In the final step, the client is extracted into the cytosol by p97 (and its cofactors), and delivered to the proteasome for degradation (step 4). Sel1L: protein sel-1 homolog 1; Hrd1: E3 ubiquitin-protein ligase synoviolin; Poly(Ub)n: polyubiquitin chain; RING: Really Interesting New Gene finger domain.

Mentions: The ER is thought to be an oxidative membrane-bound organelle that specializes in protein folding. These ER-folding clients often represent proteins that are destined for secretion along the classical secretory pathway, which is physically connected to the ER. During co-translational translocation of nascent polypeptide chains into the ER, the nascent polypeptide is transported across the ER membrane by crossing the Sec61 translocation channel [24]. In the ER, numerous ER luminal chaperones, post-translational modifiers, and folding catalysts assist in the protein folding process. For instance, carbohydrates are appended to a nascent polypeptide by the oligosaccharyl-transferase (OST) complex [25], while disulfide bonds of the polypeptide are formed and rearranged by members of the protein disulfide isomerase (PDI) family [26]. Moreover, to prevent a polypeptide chain from aggregation and render it soluble, molecular chaperones such as the 70 kDa heat shock protein (Hsc70) ATPase binding immunoglobulin protein (BiP) are recruited to the folding intermediate [27]. These coordinated efforts enable the polypeptide to attain its native configuration and proper oligomeric state. Once formed and assembled, a folded polypeptide is packaged into coat protein complex II (COPII) vesicles and exits the ER en route for secretion. Because approximately one third of all mammalian genes encode proteins that are translocated into the ER, it is not surprising that the ER maintains a quality control system that prevents the generation of misfolded or aggregated ER proteins, and has the capacity to actively remove these aberrant species should they form. Over the past two decades, ERAD has been identified as the key ER quality control process dedicated to the removal of misfolded ER proteins [28,29]. During ERAD, misfolded ER clients are recognized and ejected into the cytosol where they are in turn degraded by the ubiquitin-dependent proteasome machinery. Conceptually, the quality control process can be divided into four distinct steps: substrate recognition, retro-translocation across the ER membrane, substrate polyubiquitination, and proteasomal degradation (Figure 2).


How Polyomaviruses Exploit the ERAD Machinery to Cause Infection
ER-associated degradation (ERAD) pathway. ERAD is an ER quality control pathway that identifies and triages misfolded ER proteins. In the first step, a misfolded protein is recognized by ER-resident chaperones, which target the misfolded client to the retro-translocation machinery on the ER membrane (step 1). Next the misfolded client is retro-translocated across the ER membrane by crossing the retro-translocation channel (step 2); a major component of this channel is the Sel1L-Hrd1 membrane complex. When the client emerges into the cytosol, it is ubiquitinated by the catalytic domain of Hrd1 that faces the cytosol, eventually resulting in polyubiquitinaton of the substrate (step 3). In the final step, the client is extracted into the cytosol by p97 (and its cofactors), and delivered to the proteasome for degradation (step 4). Sel1L: protein sel-1 homolog 1; Hrd1: E3 ubiquitin-protein ligase synoviolin; Poly(Ub)n: polyubiquitin chain; RING: Really Interesting New Gene finger domain.
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viruses-08-00242-f002: ER-associated degradation (ERAD) pathway. ERAD is an ER quality control pathway that identifies and triages misfolded ER proteins. In the first step, a misfolded protein is recognized by ER-resident chaperones, which target the misfolded client to the retro-translocation machinery on the ER membrane (step 1). Next the misfolded client is retro-translocated across the ER membrane by crossing the retro-translocation channel (step 2); a major component of this channel is the Sel1L-Hrd1 membrane complex. When the client emerges into the cytosol, it is ubiquitinated by the catalytic domain of Hrd1 that faces the cytosol, eventually resulting in polyubiquitinaton of the substrate (step 3). In the final step, the client is extracted into the cytosol by p97 (and its cofactors), and delivered to the proteasome for degradation (step 4). Sel1L: protein sel-1 homolog 1; Hrd1: E3 ubiquitin-protein ligase synoviolin; Poly(Ub)n: polyubiquitin chain; RING: Really Interesting New Gene finger domain.
Mentions: The ER is thought to be an oxidative membrane-bound organelle that specializes in protein folding. These ER-folding clients often represent proteins that are destined for secretion along the classical secretory pathway, which is physically connected to the ER. During co-translational translocation of nascent polypeptide chains into the ER, the nascent polypeptide is transported across the ER membrane by crossing the Sec61 translocation channel [24]. In the ER, numerous ER luminal chaperones, post-translational modifiers, and folding catalysts assist in the protein folding process. For instance, carbohydrates are appended to a nascent polypeptide by the oligosaccharyl-transferase (OST) complex [25], while disulfide bonds of the polypeptide are formed and rearranged by members of the protein disulfide isomerase (PDI) family [26]. Moreover, to prevent a polypeptide chain from aggregation and render it soluble, molecular chaperones such as the 70 kDa heat shock protein (Hsc70) ATPase binding immunoglobulin protein (BiP) are recruited to the folding intermediate [27]. These coordinated efforts enable the polypeptide to attain its native configuration and proper oligomeric state. Once formed and assembled, a folded polypeptide is packaged into coat protein complex II (COPII) vesicles and exits the ER en route for secretion. Because approximately one third of all mammalian genes encode proteins that are translocated into the ER, it is not surprising that the ER maintains a quality control system that prevents the generation of misfolded or aggregated ER proteins, and has the capacity to actively remove these aberrant species should they form. Over the past two decades, ERAD has been identified as the key ER quality control process dedicated to the removal of misfolded ER proteins [28,29]. During ERAD, misfolded ER clients are recognized and ejected into the cytosol where they are in turn degraded by the ubiquitin-dependent proteasome machinery. Conceptually, the quality control process can be divided into four distinct steps: substrate recognition, retro-translocation across the ER membrane, substrate polyubiquitination, and proteasomal degradation (Figure 2).

View Article: PubMed Central - PubMed

ABSTRACT

To infect cells, polyomavirus (PyV) traffics from the cell surface to the endoplasmic reticulum (ER) where it hijacks elements of the ER-associated degradation (ERAD) machinery to penetrate the ER membrane and reach the cytosol. From the cytosol, the virus transports to the nucleus, enabling transcription and replication of the viral genome that leads to lytic infection or cellular transformation. How PyV exploits the ERAD machinery to cross the ER membrane and access the cytosol, a decisive infection step, remains enigmatic. However, recent studies have slowly unraveled many aspects of this process. These emerging insights should advance our efforts to develop more effective therapies against PyV-induced human diseases.

No MeSH data available.


Related in: MedlinePlus