Abstract:The protein kinase C and casein kinase 2 substrate in neurons (Pacsin) is a subfamily of membrane-binding proteins that participates in vesicle trafficking and cytoskeleton organization. Here, we studied Pacsin 2 in kidney development and repair following injury. In the postnatal developing kidneys, Pacsin 2 was found to be expressed in both ureteric bud- and mesenchyme-derived structures including proximal and distal tubules, Bowman's capsule, and the glomerular tuft. In the adult kidney, its expression was d… Show more
“…1e, Supplementary Figure 1c). PACSIN2 depletion in murine Inner Medullary Collecting Duct (mIMCD3) cells (Supplementary Figure 1d), a line thought to use the extracellular ciliogenesis pathway 6 and expressing low levels of PACSIN1 (Supplementary Figure 1e), did not affect ciliogenesis (Supplementary Figure 1f), consistent with a previous report 30 .Fig. 1PACSIN1 and -2 are required for ciliogenesis.…”
The intracellular ciliogenesis pathway requires membrane trafficking, fusion, and reorganization. Here, we demonstrate in human cells and zebrafish that the F-BAR domain containing proteins PACSIN1 and -2 play an essential role in ciliogenesis, similar to their binding partner and membrane reorganizer EHD1. In mature cilia, PACSINs and EHDs are dynamically localized to the ciliary pocket membrane (CPM) and transported away from this structure on membrane tubules along with proteins that exit the cilium. PACSINs function early in ciliogenesis at the ciliary vesicle (CV) stage to promote mother centriole to basal body transition. Remarkably, we show that PACSIN1 and EHD1 assemble membrane tubules from the developing intracellular cilium that attach to the plasma membrane, creating an extracellular membrane channel (EMC) to the outside of the cell.
“…1e, Supplementary Figure 1c). PACSIN2 depletion in murine Inner Medullary Collecting Duct (mIMCD3) cells (Supplementary Figure 1d), a line thought to use the extracellular ciliogenesis pathway 6 and expressing low levels of PACSIN1 (Supplementary Figure 1e), did not affect ciliogenesis (Supplementary Figure 1f), consistent with a previous report 30 .Fig. 1PACSIN1 and -2 are required for ciliogenesis.…”
The intracellular ciliogenesis pathway requires membrane trafficking, fusion, and reorganization. Here, we demonstrate in human cells and zebrafish that the F-BAR domain containing proteins PACSIN1 and -2 play an essential role in ciliogenesis, similar to their binding partner and membrane reorganizer EHD1. In mature cilia, PACSINs and EHDs are dynamically localized to the ciliary pocket membrane (CPM) and transported away from this structure on membrane tubules along with proteins that exit the cilium. PACSINs function early in ciliogenesis at the ciliary vesicle (CV) stage to promote mother centriole to basal body transition. Remarkably, we show that PACSIN1 and EHD1 assemble membrane tubules from the developing intracellular cilium that attach to the plasma membrane, creating an extracellular membrane channel (EMC) to the outside of the cell.
“…Nonetheless, PACSIN2 may associate with renal pathophysiology, as suggested by our study and others. Indeed, PACSIN2 expression is elevated in proximal and collecting tubules in a model of ischemia‐reperfusion injury, reflecting a potential role in tubulogenesis (15). In tubular cells, PACSIN2 also interacts with polycystin‐1, which is mutated in polycystic kidney disease, further supporting a role for PACSIN2 in the maintenance of renal function (44).…”
Section: Discussionmentioning
confidence: 99%
“…B, C ) Scoring of PACSIN2 staining intensity in glomeruli of 8-wk-old (B) and 34-wk-old (C ) ZDF rats, from 0 (negative) to 5 (strong staining). Each data point represents the average score of all glomeruli (15)(16)(17)(18)(19)(20)(21)(22)(23)(24) analyzed in each rat (n = 6-8). At both 8 and 34 wk, glomeruli of obese rats showed elevated PACSIN2 staining compared with lean control rats.…”
Section: Pacsin2 Expression Is Elevated In Podocytes Of Obese and Diamentioning
confidence: 99%
“…Specifically, PACSIN2 has an F‐BAR domain, which induces negative curvature to membranes, and NPF motifs and an SH3 domain that bind to cytoskeletal, endocytic and recycling proteins (12, 13, 14). In kidney, PACSIN2 is expressed in tubules, where it participates in repair processes after ischemia‐reperfusion injury (15). PACSIN2 is also present in podocytes (15), yet its function has remained uncharacterized.…”
mentioning
confidence: 99%
“…In kidney, PACSIN2 is expressed in tubules, where it participates in repair processes after ischemia‐reperfusion injury (15). PACSIN2 is also present in podocytes (15), yet its function has remained uncharacterized. In this study, we investigate whether PACSIN2 regulates the trafficking of nephrin and whether PAC‐SIN2 expression changes in DKD.…”
Nephrin is a core component of podocyte (glomerular epithelial cell) slit diaphragm and is required for kidney ultrafiltration. Down-regulation or mislocalization of nephrin has been observed in diabetic kidney disease (DKD), characterized by albuminuria. Here, we investigate the role of protein kinase C and casein kinase 2 substrate in neurons 2 (PACSIN2), a regulator of endocytosis and recycling, in the trafficking of nephrin and development of DKD. We observe that PACSIN2 is up-regulated and nephrin mislocalized in podocytes of obese Zucker diabetic fatty (ZDF) rats that have altered renal function. In cultured podocytes, PACSIN2 and nephrin colocalize and interact. We show that nephrin is endocytosed in PACSIN2-positive membrane regions and that PACSIN2 overexpression increases both nephrin endocytosis and recycling. We identify rabenosyn-5, which is involved in early endosome maturation and endosomal sorting, as a novel interaction partner of PACSIN2. Interestingly, rabenosyn-5 expression is increased in podocytes in obese ZDF rats, and, in vitro, its overexpression enhances the association of PACSIN2 and nephrin. We also show that palmitate, which is elevated in diabetes, enhances this association. Collectively, PACSIN2 is up-regulated and nephrin is abnormally localized in podocytes of diabetic ZDF rats. In vitro, PACSIN2 enhances nephrin turnover apparently via a mechanism involving rabenosyn-5. The data suggest that elevated PACSIN2 expression accelerates nephrin trafficking and associates with albuminuria
The BAR domain is the eponymous domain of the “BAR-domain protein superfamily”, a large and diverse set of mostly multi-domain proteins that play eminent roles at the membrane cytoskeleton interface. BAR domain homodimers are the functional units that peripherally associate with lipid membranes and are involved in membrane sculpting activities. Differences in their intrinsic curvatures and lipid-binding properties account for a large variety in membrane modulating properties. Membrane activities of BAR domains are further modified and regulated by intramolecular or inter-subunit domains, by intermolecular protein interactions, and by posttranslational modifications. Rather than providing detailed cell biological information on single members of this superfamily, this review focuses on biochemical, biophysical, and structural aspects and on recent findings that paradigmatically promote our understanding of processes driven and modulated by BAR domains.
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