A PLA1-2 punch regulates the Golgi complex

Abstract

The mammalian Golgi complex, trans Golgi network (TGN) and ER-Golgi intermediate compartment (ERGIC) are comprised of membrane cisternae, coated vesicles and membrane tubules, all of which contribute to membrane trafficking and maintenance of their unique architectures. Recently, a new cast of players was discovered to regulate the Golgi and ERGIC: four unrelated cytoplasmic phospholipase A (PLA) enzymes, cPLA(2)α (GIVA cPLA(2)), PAFAH Ib (GVIII PLA(2)), iPLA(2)-β (GVIA-2 iPLA(2)) and iPLA(1)γ. These ubiquitously expressed enzymes regulate membrane trafficking from specific Golgi subcompartments, although there is evidence for some functional redundancy between PAFAH Ib and cPLA(2)α. Three of these enzymes, PAFAH Ib, cPLA(2)α and iPLA(2)-β, exert effects on Golgi structure and function by inducing the formation of membrane tubules. We review our current understanding of how PLA enzymes regulate Golgi and ERGIC morphology and function.

Figure I

A simplified diagram of the Golgi complex as a hub of membrane trafficking.

Figure 1. Domain structures of Golgi- and ERGIC-associated PLA enzymes

cPLA₂α contains a large α/β hydrolase domain with residues S228 and D549 comprising the active site dyad. It also contains a C2 Ca²⁺-binding domain that is necessary for translocation to Golgi membranes. PAFAH Ib is comprised of α1 and α2 homo- or heterodimers together with LIS1. The indicated residues form the active site triad. iPLA₂–β contains a patatin lipase domain, with an active site at S519, and seven ankyrin repeats (I-VII). iPLA₁γ contains an S351 residue, which when mutated to alanine (A) abolishes catalytic activity, a DDHD2 domain that is conserved with iPLA₁β, a WWE domain predicted to mediate protein-protein interactions in ubiquitination and ADP-ribosylation systems, and a SAM domain (sterile alpha motif) that can mediate both homo- and hetero-oligomerization.

Figure 2. PLA enzymes that regulate the structure and function of the Golgi complex and endosomes

cPLA₂α localizes to the Golgi complex and mediates the formation of membrane tubules that facilitate anterograde transport through the cisternal stack. The α1 and α2 PLA₂ catalytic subunits of PAFAH Ib localize to multiple Golgi cisternae, early sorting endosomes (ESEs), and the endocytic recycling compartment (ERC). These enzymes contribute to membrane tubule formation that links cisternal stacks into intact Golgi ribbons and to those that facilitate endocytic recycling of transferrin and its receptor from ESEs and the ERC. In addition, loss of α1 and α2 inhibits export from the TGN, although it is not clear if this involves membrane tubules. iPLA₂–β localizes specifically to the ERGIC where it mediates the formation of membrane tubules that bridge between separate ERGIC clusters. iPLA₁γ appears to localize primarily to the cis Golgi and may influence anterograde transport through the cisternal stack.

Figure 3. Model integrating membrane curvature produced by the PLA₂ activity of PAFAH Ib α1 and α2 with Lis1-mediated dynein transport along microtubules

PAFAHIB initiates outward membrane curvature to generate a membrane tubule, which can be pulled/extended along microtubules (MT) by Lis1 and Ndel interactions with dynein. Dynein may be able to carry the membrane tubule towards the minus end of microtubules, facilitating the convergence of the Golgi stack and positioning at the microtubule organizing center (MTOC, minus end of the microtubules).