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DYRK3-Controlled Phase Separation Organizes the Early Secretory Pathway

Raffaella Gallo, Arpan Rai, Lucas Pelkmans

Preprint posted on February 10, 2020 https://www.biorxiv.org/content/10.1101/2020.02.10.941757v1

How are ER and Golgi membranes intimately and dynamically linked, whilst remaining distinct? Answer: Liquid-liquid phase separation

Selected by Helen Zenner, Nicola Stevenson

Categories: cell biology

Background

Liquid-liquid phase separation (LLPS) is important for regulating the clustering of proteins and membranes in a variety of sub-cellular structures from P-bodies, to stress granules and even has a role in virus assembly1.  More recently it has been suggested that LLPS could be involved in Golgi organisation via the matrix proteins2. The proteins that organise the formation of LLPS-dependent structures share a key feature, intrinsic disordered regions (IDR).  These regions can interact with each other via weak multivalent interactions and because the interactions are weak, the proteins within the condensate can rapidly exchange with the cytosol, thus giving them liquid-like properties. The interactions within the condensates are further regulated by phosphorylation creating a dynamically organised system.  A key kinase in regulating many of the previously described intracellular condensates is Dual specificity tyrosine regulated kinase 3 (DYRK3).

The Pelkmans group has previously identified proteins of the early secretory pathway3as some of the top hits in the interactome of DYRK34.  The secretory pathway is composed of a series of membrane bound compartments which act as a manufacturing conveyor belt for proteins that need to be secreted. Secreted proteins are synthesised in the endoplasmic reticulum (ER) before being concentrated and sorted into specific domains known as ER exit sites (ERES). From here they bud from the ER in COPII coated vesicles which coalesce to form the ER-Golgi-intermediate compartment (ERGIC), which fuses with the cis-face of the Golgi apparatus. The proteins then proceed through a series of flattened membrane bound cisternae in which they are modified before being sorted and packaged again at the trans-face of the Golgi for transport to the plasma membrane.

Membrane and protein flux through the secretory pathway must be tightly organised at each step to ensure efficient secretion and to maintain the structural integrity of the organelles themselves. One protein responsible for organising ERES, Sec16A, contains IDRs and was one of the DYRK3 interactors identified by the Pelkman group. Other components of the ERES machinery such as TANGO1L and cTAGE5 similarly contain IDRs. Thus, LLPS provides an attractive hypothesis to explain how ERES proteins, COPII and even Golgi components are organised.

Key findings

In the highlighted preprint, the authors demonstrate a role for LLPS in the organisation and function of the early secretory pathway.  These are their key findings:

  • Inhibition or overexpression of DYRK3 leads to perturbation of ERES as well as the relationships between ERES, ERGIC and cis-Golgi. Specifically, loss of DYRK3 kinase activity results in the condensation of Sec16, ERGIC53 and GM130 positive structures in the perinuclear region, whilst over expression causes dispersal of ERES
  • Perturbations of secretory pathway organisation following changes in DYRK3 activity disrupt anterograde trafficking
  • Overexpression of Sec16A IDR is sufficient to form aberrant spherical condensates containing other proteins of the early secretory pathway
  • DYRK3 directly phosphorylates Sec16A and is important for the dynamics of the condensates
  • The tyrosine-rich domain of Sec16A is required for self-interaction in condensates and the recruitment of binding partners carrying a proline-rich domain

Overall, this study provides some original ideas on secretory pathway organisation. The research shows that the dynamic nature of the LLPS of ERES and Golgi components, as regulated by Sec16A LDR and DYRK3, is essential for both a functional secretory pathway and in maintaining distinct but interlinked organelles.

Questions

  1. Since DYRK3 is involved in the dissolution of membraneless organelles during mitosis, and likewise the Golgi ribbon and the associated ERES have to be disassembled during cell division, could DYRK3 also play a role in this process?
  2. Is LLPS separation required for unconventional secretion, where CFTR exits the ER in a Sec16A, but COPII independent manner?
  3. How is DYRK3 regulated?
  4. What is the relationship between these condensates containing secretory membranes and the membrane-less Sec16 containing Sec bodies induced under stress? How might cells regulate which is formed?

For more information

  1. A review of LLPS – Alberti et al., 2019, Cell
  2. LLPS and the Golgi – Rebane et al., 2019 and Rothman, 2019, both FEBS Letters
  3. A review of the early secretory pathway – Peotter et al, 2019, Traffic
  4. Interactome of DYRK3 – Rai et al, 2018, Nature

Tags: dyrk3, phase separation, secretory pathway, trafficking

Posted on: 26th March 2020

doi: https://doi.org/10.1242/prelights.17947

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