ARPCOMPLEXITY

ERC funded synergy grant defining the role of Arp2/3 complex isoforms at multiple scales of biology

The Arp2/3 complex consisting of seven subunits (Arp2, Arp3 and ARPC1–5) is conserved from yeast to man and plays an essential role in generating branched actin filament networks that provide the driving force and structural support for the physical integrity of cells, and a wide range of fundamental cellular processes including membrane trafficking and cell migration.

Interestingly, in humans and other mammals, Arp3, ARPC1 and ARPC5 exist as two different isoforms (Arp3/Arp3B, ARPC1A/ARPC1B and ARPC5/ARPC5L) that are 91, 67 and 67% identical respectively. The presence of these subunit isoforms suggests that the mammalian Arp2/3 complex is actually a family of 8 iso-complexes with specific cellular or physiological functions.  

​

The Way lab previously demonstrated that ARPC1 and ARPC5 isoforms confer different actin nucleating properties to the Arp2/3 complex (Abella 2016, PMID:26655834). We have also established that Arp3 and Arp3B containing complexes have different cellular properties, with those with Arp3B enhancing branched actin network disassembly (Galloni 2021, PMID: 34106209).  In addition, the Gomes lab has demonstrated that the ARPC5 isoforms play unique roles in T-tubule organization and nuclei positioning in skeletal muscle (Roman 2017, PMID:28892082).  

The importance of Arp2/3 isoforms in tissue homeostasis is also underscored by the finding that loss of function mutations in human ARPC1B lead to Wiskott-Aldrich syndrome like symptoms including severe inflammation and immunodeficiency as well as impaired cytotoxic T lymphocyte maintenance and cytolytic activity (Kahr 2017 PMID:28368018 and Randzavola 2019, PMID:31710310).

​

The task ahead is to investigate whether the eight different Arp2/3 complexes have unique activities, interactions, cellular or physiological functions. ARPComplexity is an ERC funded synergy grant involving the labs of Michael Way (Crick Institute London), Carolyn Moores (Birkbeck College, London) and Edgar Gomes (IMM, Lisbon, Portugal).  We aim to understand the role of Arp2/3 complex diversity at three hierarchies of biology (molecular, cellular and physiological).