Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

Sarma, Jayasri Das; Kaplan, Benjamin E.; Willemsen, Dounia; Koval, Michael

doi:10.1080/15419060802014305

Cited by 33 publications

(28 citation statements)

References 64 publications

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“…Importantly, 4-PBA improves the trafficking of several mutant transmembrane proteins, including the ⌬F508 mutant of cystic fibrosis transmembrane regulator (CFTR) (Rubenstein et al, 1997). We found that 4-PBA enhanced the ability of HeLa cells to process overexpressed Cx43 that would otherwise saturate the quality control pathway in these cells Das Sarma et al, 2008). Because 4-PBA alters protein expression, these observations suggested that the ability of 4-PBA to compensate for Cx43 overexpression was because of the increased expression of one or more elements of the connexin quality control pathway.…”

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confidence: 87%

ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

Das

Smith

Sarma

et al. 2009

MBoC

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Connexin43 (Cx43) is a gap junction protein that forms multimeric channels that enable intercellular communication through the direct transfer of signals and metabolites. Although most multimeric protein complexes form in the endoplasmic reticulum (ER), Cx43 seems to exit from the ER as monomers and subsequently oligomerizes in the Golgi complex. This suggests that one or more protein chaperones inhibit premature Cx43 oligomerization in the ER. Here, we provide evidence that an ER-localized, 29-kDa thioredoxin-family protein (ERp29) regulates Cx43 trafficking and function. Interfering with ERp29 function destabilized monomeric Cx43 oligomerization in the ER, caused increased Cx43 accumulation in the Golgi apparatus, reduced transport of Cx43 to the plasma membrane, and inhibited gap junctional communication. ERp29 also formed a specific complex with monomeric Cx43. Together, this supports a new role for ERp29 as a chaperone that helps stabilize monomeric Cx43 to enable oligomerization to occur in the Golgi apparatus. INTRODUCTIONConnexins form gap junction channels that mediate intercellular communication by allowing the direct transfer of ions and small aqueous molecules between neighboring cells or by serving as hemichannels at the plasma membrane (Harris, 2001;Goodenough and Paul, 2003;Saez et al., 2003;Laird, 2006). There are Ͼ20 human connexin genes and one of the most ubiquitously expressed is connexin43 (Cx43). Several diseases have been linked to mutations in different connexin genes, including Cx43 (Kelsell et al., 2001;Laird, 2008). Many of these mutant connexins are not efficiently processed and lack the ability to form functional gap junction channels. Determining how mutant connexins are mistargeted requires a more complete understanding of how normal connexins are processed by the cell.A gap junction hemichannel consists of six connexins, which oligomerize before delivery to the plasma membrane (Martin and Evans, 2004;Segretain and Falk, 2004;Koval, 2006). Unlike most multimeric membrane channels, Cx43 is unusual in that it does not oligomerize in the endoplasmic reticulum (ER) (Musil and Goodenough, 1993), which is more commonly a prerequisite to further transport along the secretory pathway (Ellgaard and Helenius, 2003;Anelli and Sitia, 2008). Instead, Cx43 is transported out of the ER as an apparent monomer that then oligomerizes in the Golgi complex (Musil and Goodenough, 1993;Koval et al., 1997). Although other connexins, such as Cx46 (Koval et al., 1997), also oligomerize in the Golgi apparatus, this is not a universal pathway for connexin oligomerization because other gap junction proteins, such as Cx32, preferentially oligomerize in the ER (Martin and Evans, 2004;Koval, 2006). Understanding the molecular basis for this difference, as well as the ability of monomeric Cx43 to be transported from the ER to the Golgi apparatus has proven difficult, because little is known about chaperones that regulate connexin folding. In particular, it seemed likely that one or more chaperones would be requir...

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confidence: 87%

ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

Das

Smith

Sarma

et al. 2009

MBoC

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“…The trafficking of Cx43 in monomer form to the TGN is facilitated through interactions with the GTPase protein rab20 (Das Sarma et al, 2008). By use of GST pull-down or yeast-2-hybrid assays, connexins have also been found to specifically interact with consortin within the TGN.…”

Section: A Gap Junction Channelsmentioning

confidence: 99%

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

et al. 2014

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“…One such member is Rab20, which is mainly expressed in the apical side of kidney tubule, intestine epithelial cells and non-polarized cells [21], [22]. It is known that Rab20 localizes in the Golgi, ER region and some endocytic compartments, however its function remains uncharacterized [21], [23], [24]. Most recently, it has been shown that Rab20 is recruited to phagolysosomes containing Staphylococcus aureus , whereas it is dissociated from phagosomes containing Mycobacterium tuberculosis , which arrests phagosome maturation [25].…”

Section: Introductionmentioning

confidence: 99%

Rab20 Regulates Phagosome Maturation in RAW264 Macrophages during Fc Gamma Receptor-Mediated Phagocytosis

Egami¹,

Araki

2012

PLoS ONE

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Rab20, a member of the Rab GTPase family, is known to be involved in membrane trafficking, however its implication in FcγR-mediated phagocytosis is unclear. We examined the spatiotemporal localization of Rab20 during phagocytosis of IgG-opsonized erythrocytes (IgG-Es) in RAW264 macrophages. By the live-cell imaging of fluorescent protein-fused Rab20, it was shown that Rab20 was transiently associated with the phagosomal membranes. During the early stage of phagosome formation, Rab20 was not localized on the membranes of phagocytic cups, but was gradually recruited to the newly formed phagosomes. Although Rab20 was colocalized with Rab5 to some extent, the association of Rab20 with the phagosomes persisted even after the loss of Rab5 from the phagosomal membranes. Then, Rab20 was colocalized with Rab7 and Lamp1, late endosomal/lysosomal markers, on the internalized phagosomes. Moreover, our analysis of Rab20 mutant expression revealed that the maturation of phagosomes was significantly delayed in cells expressing the GDP-bound mutant Rab20-T19N. These data suggest that Rab20 is an important component of phagosome and regulates the phagosome maturation during FcγR-mediated phagocytosis.

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Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

Cited by 33 publications

References 64 publications

ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

Rab20 Regulates Phagosome Maturation in RAW264 Macrophages during Fc Gamma Receptor-Mediated Phagocytosis

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