The PKD-Dependent Biogenesis of TGN-to-Plasma Membrane Transport Carriers

Abstract

Membrane trafficking is essential for processing and transport of proteins and lipids and to establish cell compartmentation and tissue organization. Cells respond to their needs and control the quantity and quality of protein secretion accordingly. In this review, we focus on a particular membrane trafficking route from the trans-Golgi network (TGN) to the cell surface: protein kinase D (PKD)-dependent pathway for constitutive secretion mediated by carriers of the TGN to the cell surface (CARTS). Recent findings highlight the importance of lipid signaling by organelle membrane contact sites (MCSs) in this pathway. Finally, we discuss our current understanding of multiple signaling pathways for membrane trafficking regulation mediated by PKD, G protein-coupled receptors (GPCRs), growth factors, metabolites, and mechanosensors.

Sorting of secretory proteins at the trans-Golgi network by human TGN46

“…The kinase activity of protein kinase D (PKD) is required for severing CARTS from the TGN 33 . Expression of a kinase-dead mutant of PKD (PKD-KD) induces formation of cargo-containing tubules (fission-defective CARTS precursors) at the TGN 2,39 . We took advantage of this finding to investigate the role of TGN46 in PAUF export in CARTS.…”

“…Although a number of sequence motifs have been reported to serve as retention signals for Golgi-resident proteins 41,42 , less is known about how cargoes are selectively sorted into transport carriers budding at the TGN. Particularly, no sorting mechanism has been reported for CARTS-specific cargoes 2 . To gain insight into how TGN46 drives selective cargo incorporation into nascent transport carriers, we asked whether TGN46 contains dedicated topological determinants (such as domains, regions, or motifs) for its cargo sorting/packaging function.…”

“…It is possible that developing various TGN-to-plasma membrane export routes of different kinetics might have endowed cells with beneficial mechanisms to cope with their secretory needs under stress conditions. CARTS have been suggested to be enriched in cholesterol and SM 2,77 , and their biogenesis to require intact ER-Golgi membrane contact sites (MCS) supplying the TGN with these lipids (or their precursors) 77,78 . Notably, data from Deng, Pakdel et al suggested that TGN46 is a native cargo of the SM-dependent TGN export pathway, as it was identified by mass spectrometry of to be co-packaged in carriers containing the lumenal SM sensor EQ-SM-APEX2 20 .…”

“…Biosynthetic secretory cargoes are made in the ER and transported to the Golgi apparatus, where they are further processed and eventually sorted at the trans-Golgi network (TGN) for delivery to their respective destinations [1][2][3][4][5] . The accurate and timely export of cargo proteins is essential for the maintenance of cell and tissue homeostasis, and, accordingly, errors in this process can have severe physiological and pathophysiological consequences 6 .…”

“…TGN46 exits the TGN in specific carriers called CARTS (carriers of the TGN to the cell surface). Protein kinase D (PKD), known for its role in events leading to the fission of cargo-containing carriers at the TGN, is required for the production of CARTS 2,[33][34][35] . How secretory cargoes are sorted and specifically packed into CARTS is not known.…”