Dimerization of ERp29, a PDI-like Protein, Is Essential for Its Diverse Functions

Abstract

Protein disulfide isomerase (PDI)-like proteins act as oxido-reductases and chaperones in the endoplasmic reticulum (ER).How oligomerization of the PDI-like proteins control these activities is unknown. Here we show that dimerization of ERp29, a PDI-like protein, regulates its protein unfolding and escort activities. We have demonstrated previously that ERp29 induces the local unfolding of polyomavirus in the ER, a step required for viral infection. We now find that, in contrast to wild-type ERp29, a mutant ERp29 (D42A) that dimerizes inefficiently is unable to unfold polyomavirus or stimulate infection. A compensatory mutation that partially restores dimerization to the mutant ERp29 (G37D/D42A) rescues ERp29 activity. These results indicate that dimerization of ERp29 is crucial for its protein unfolding function. ERp29 was also suggested to act as an escort factor by binding to the secretory protein thyroglobulin (Tg) in the ER, thereby facilitating its secretion. We show that this escort function likewise depends on ERp29 dimerization. Thus our data demonstrate that dimerization of a PDI-like protein acts to regulate its diverse ER activities.

ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

“…ERp29 has also been shown to promote the folding and secretion of thyroglobulin (Sargsyan et al, 2002;Baryshev et al, 2006) and the Drosophila paralogue of ERp29, Windbeutel, is required for transport of heparan sulfate 2-O-sulfotransferase (Pipe) from the ER to the Golgi apparatus (Ma et al, 2003). ERp29 also facilitates the unfolding and ER retrotranslocation of the polyomavirus VP1 protein, a key step in the virus infection cycle (Magnuson et al, 2005;Rainey-Barger et al, 2007).…”

“…ERp29 has also been shown to promote the folding and secretion of thyroglobulin (Sargsyan et al, 2002;Baryshev et al, 2006) and the Drosophila paralogue of ERp29, Windbeutel, is required for transport of heparan sulfate 2-O-sulfotransferase (Pipe) from the ER to the Golgi apparatus (Ma et al, 2003). ERp29 also facilitates the unfolding and ER retrotranslocation of the polyomavirus VP1 protein, a key step in the virus infection cycle (Magnuson et al, 2005;Rainey-Barger et al, 2007).The emerging role for ERp29 in regulating protein trafficking suggests the possibility of an analogous role for ERp29 in regulating Cx43 transport along the secretory pathway. Here, we provide evidence that ERp29 stabilizes monomeric Cx43 in the ER and that interference with ERp29 expression inhibited Cx43 secretion and decreased the efficiency of gap junction formation by Cx43.…”

A PDI Family Network Acts Distinctly and Coordinately with ERp29 To Facilitate Polyomavirus Infection

“…From the cytosol, Py is transferred into the nucleus, with the ensuing transcription and replication of the viral genome leading to lytic infection or cell transformation. How Py is transported across the ER membrane from the ER lumen into the cytosol is a complicated process that recent studies have begun to unravel (6,10,11,(17)(18)(19).…”

How Viruses Use the Endoplasmic Reticulum for Entry, Replication, and Assembly

“…2A, step 2) (Daniels et al 2006;Rainey-Barger et al 2007b;Geiger et al 2011). At this juncture, ERAD membrane components including Derlin-1 (Schelhaas et al 2007;Jiang et al 2009b), Derlin-2 (Lilley et al 2006), Sel1L (Schelhaas et al 2007), RMA1 (Geiger et al 2011), and BAP29/BAP31 (Geiger et al 2011), have been proposed to facilitate Py's exit to the cytosol.…”