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 means that the mammalian Arp2/3 complex is actually a family of 8 iso-complexes.  We have previously demonstrated that these isoforms confer different properties to the Arp2/3 complex which result in differences in both the assembly and disassembly of actin networks (Abella et al., 2016 - PMID:26655834; Galloni et al., 2021 - PMID:34106209; Cao et al., 2024 PMID:39009834 and Cao et al., BioRxiv. https://doi.org/10.64898/2025.12.01.691495).  
 
The importance of Arp2/3 complex subunit isoforms is evident from the observation that loss of human ARPC1B results in severe inflammation and immunodeficiency (PMID:28368018). In collaboration with clinicians, we have also found that loss of function mutations in ARPC5 lead to immune disease, multiple congenital anomalies, and early postnatal death (Sindram et al., 2023 - PMID:37382373).  More recently, by deleting ARPC5 in the murine hematopoietic system, we uncovered why patients lacking ARPC5 develop gastrointestinal complications, immunodeficiency and are prone to fatal sepsis (Vasconcellos et al., 2025 PMID:41231985).  Specifically, macrophages lacking Arpc5-, but not Arpc5l-, containing Arp2/3 complexes are unable to maintain host-microbiota homeostasis as they are deficient in phagocytosing and killing intra-cellular bacteria. In addition, the Gomes lab has demonstrated that the ARPC5 also modulates T-tubule organization in skeletal muscle by regulating cortical actin (Roman et al., 2017- PMID:28892082, Pereira, et al., 2025 BioRxiv. https://doi.org/10.1101/2024.08.13.607563)
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ARPComplexity is an ERC funded synergy grant involving the labs of Michael Way (Crick Institute, London: https://www.crick.ac.uk/), Carolyn Moores (Birkbeck College, London: https://www.bbk.ac.uk/our-staff/profile/8004606/carolyn-moores) and Edgar Gomes (GIMM, Lisbon, Portugal: https://gimm.pt/lab/edgar-gomes-lab/). investigating the unique activities, interactions, cellular and physiological functions of Arp2/3 iso-complexes