Branching out in different directions: Emerging cellular functions for the Arp2/3 complex and WASP-family actin nucleation factors

Campellone, Kenneth; Lebek, Nadine M; King, Virginia L

doi:10.1016/j.ejcb.2023.151301

Cited by 17 publications

(19 citation statements)

References 401 publications

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“…The Arp2/3 complex is required for autophagic membrane turnover Multiple nucleation-promoting factors including WHAMM, JMY, WASH, and Cortactin participate in assembling actin filaments at phagophores, autophagosomes, or autolysosomes (Campellone et al, 2023;Kramer et al, 2022). These observations led us to question where and when the Arp2/3 complex has the greatest impact on autophagy.…”

Section: Resultsmentioning

confidence: 99%

Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity

Theodore,

Wagner,

Campellone

2024

Preprint

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Autophagy is an intracellular degradation process that maintains homeostasis, responds to stress, and plays key roles in the prevention of aging and disease. Autophagosome biogenesis, vesicle rocketing, and autolysosome tubulation are controlled by multiple actin nucleation factors, but the impact of actin assembly on completion of the autophagic pathway is not well understood. Here we studied autophagosome and lysosome remodeling in fibroblasts harboring an inducible knockout (iKO) of the Arp2/3 complex, an essential actin nucleator. Arp2/3 complex ablation resulted in increased basal levels of autophagy receptors and lipidated membrane proteins from the LC3 and GABARAP families. Under both steady-state and starvation conditions, Arp2/3 iKO cells accumulated abnormally high numbers of autolysosomes, suggesting a defect in autophagic flux. The inability of Arp2/3 complex-deficient cells to complete autolysosome degradation and turnover is explained by the presence of damaged, leaky lysosomes. In cells treated with an acute lysosomal membrane-damaging agent, the Arp2/3-activating protein WHAMM is recruited to lysosomes, where Arp2/3 complex-dependent actin assembly is crucial for restoring intact lysosomal structure. These results establish the Arp2/3 complex as a central player late in the canonical autophagy pathway and reveal a new role for the actin nucleation machinery in maintaining lysosomal integrity.

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Section: Resultsmentioning

confidence: 99%

Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity

Theodore,

Wagner,

Campellone

2024

Preprint

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“…These subunits differ markedly on a sequence level from their canonical counterparts, yet their structural core is conserved. Canonical Arp2/3 complexes are recruited and activated by nucleation promoting factors (NPFs) that either belong to the Wiscott-Aldrich Syndrome Protein (WASP) or the WISH/DIP1/SPIN90 (WDS) family ( 7 ). However, we could not identify any orthologues to these proteins in the Plasmodium genomes ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

“…One third of the predicted Plasmodium proteins have no homology outside of apicomplexans (2). In addition, evolutionary conserved proteins and protein complexes governing fundamental biological processes can be hard to recognize, such as the nuclear porins (3), or they are thought to be absent, such as the spindle assembly checkpoint (4)(5)(6) or the actin nucleator actin-related protein 2/3 (Arp2/3) complex (7)(8)(9)(10)(11)(12). Plasmodium parasites undergo gamete formation and sexual replication in the mosquito.…”

Section: Introductionmentioning

confidence: 99%

“…The actin-related protein 2/3 (Arp2/3) complex is a seven-subunit complex consisting of Arp2, Arp3 and five supporting subunits ARPC1-5 that together nucleate actin filaments (8)(9)(10). In the cytoplasm of most metazoa, the Arp2/3 complex mediates lamellipodia formation and endocytic trafficking, among other processes (7,8). Nuclear functions of Arp2/3 are less well studied and differ between species, but they include DNA damage repair, nucleation of spindle actin during mitosis and meiosis and chromosome capture and segregation (18)(19)(20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

“…Nuclear functions of Arp2/3 are less well studied and differ between species, but they include DNA damage repair, nucleation of spindle actin during mitosis and meiosis and chromosome capture and segregation (18)(19)(20)(21)(22)(23)(24). Despite the evolutionary conservation of Arp2/3 across the eukaryotic kingdom (7,25), it was assumed that the complex has been lost in apicomplexan species, except for a single subunit, annotated as ARPC1/ARC40 in Plasmodium (11,12). Here we discovered that Plasmodium ARPC1 constitutes part of a highly divergent, non-canonical Arp2/3 complex, which associates with mitotic spindles in activated male gametocytes and is essential for genome segregation into budding gametes.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A non-canonical Arp2/3 complex is essential forPlasmodiumDNA segregation and transmission of malaria

Hentzschel,

Jewanski,

Sokolowski

et al. 2023

Preprint

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The malaria-causing parasite Plasmodium has a complex life cycle involving both vertebrate and mosquito hosts. Sexual stages or gametocytes are the only stage competent for transmission to mosquitoes. Formation of flagellated male gametes from gametocytes requires rapid rounds of genome replication. Here we discovered a non-canonical Plasmodium actin-related protein 2/3 (Arp2/3) complex essential for DNA segregation during male gametogenesis. Plasmodium Arp2/3 dynamically localizes within the nucleus to the endomitotic spindles and interacts with a kinetochore protein. Deletion of key Arp2/3 subunits or interfering with actin polymerisation leads to the formation of sub-haploid male gametes and a complete block in transmission through delayed developmental arrest at the oocyst stage. Our work identified an evolutionary divergent protein complex in malaria parasites that offers potential targets for transmission-blocking interventions.

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Reconstitution of Arp2/3-nucleated actin assembly with proteins CP, V-1, and CARMIL

Mooren,

McConnell,

DeBrecht

et al. 2024

Current Biology

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Branching out in different directions: Emerging cellular functions for the Arp2/3 complex and WASP-family actin nucleation factors

Cited by 17 publications

References 401 publications

Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity

Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity

A non-canonical Arp2/3 complex is essential forPlasmodiumDNA segregation and transmission of malaria

Reconstitution of Arp2/3-nucleated actin assembly with proteins CP, V-1, and CARMIL

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