Profilin connects actin assembly with microtubule dynamics

Nejedlá, Michaela; Sadi, Sara; Sulimenko, Vadym; Almeida, Francisca Nunes de; Blom, Hans; Dráber, Pavel; Aspenström, Pontus; Karlsson, Roger

doi:10.1091/mbc.e15-11-0799

Cited by 52 publications

(78 citation statements)

References 79 publications

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“…Through these two interactions, Profilin enhances the growth rate of actin filaments [1,16,17] and plays a critical role in distributing monomers between different actin nucleation systems [2,13,14,18,19]. In addition to its well-established roles in regulating actin dynamics, Profilin can influence microtubule (MT) organization and dynamics in vivo [4,20]. Further, tubulin and MT-associated proteins have been identified as potential Profilin binding partners on affinity columns [19], and Profilin has been visualized on the sides of MTs in cells using immunofluorescence following extraction to remove unbound cytosolic Profilin [4].…”

Section: Resultsmentioning

confidence: 99%

“…In addition to its well-established roles in regulating actin dynamics, Profilin can influence microtubule (MT) organization and dynamics in vivo [4,20]. Further, tubulin and MT-associated proteins have been identified as potential Profilin binding partners on affinity columns [19], and Profilin has been visualized on the sides of MTs in cells using immunofluorescence following extraction to remove unbound cytosolic Profilin [4]. Recent in vivo studies suggest that some of these MT regulatory effects may be indirect, mediated by interactions between Profilin and Formins, which in turn bind MTs [4,20,21].…”

Section: Resultsmentioning

confidence: 99%

“…Expression of R88E PFN1 led to an increase in filopodia number similar to wildtype PFN1, but elicited an even greater increase in MTs entering filopodia and average filopodial lifetime. These results suggest that the loss of actin binding in the R88E mutant may cause additional cytoskeletal defects that impact filopodial formation and stability, possibly through Profilin-Formin interactions affecting the MT cytoskeleton [4,21]. …”

Section: Resultsmentioning

confidence: 99%

“…However, a recent study showed that RNAi silencing of PFN1 in B16 melanoma cells also increases MT plus end velocities [4]. At first glance, these two observations seem to be at odds with each other.…”

Section: Resultsmentioning

confidence: 99%

“…However, Profilin also influences microtubule dynamics in cells, which may be mediated in part through its interactions with Formins that in turn bind microtubules [3,4]. Specific residues on human Profilin-1 (PFN1) are mutated in patients with amyotrophic lateral sclerosis (ALS) [5,6].…”

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confidence: 99%

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Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis

2017

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SUMMARY Profilin is an abundant actin monomer binding protein with critical actin regulatory roles in vivo [1,2]. However, Profilin also influences microtubule dynamics in cells, which may be mediated in part through its interactions with Formins that in turn bind microtubules [3,4]. Specific residues on human Profilin-1 (PFN1) are mutated in patients with amyotrophic lateral sclerosis (ALS) [5,6]. However, the observation that some ALS-linked PFN1 mutants fail to alter cellular actin organization or dynamics [5–8] or in vitro actin-monomer affinity [9] has been perplexing, given that Profilin is best understood as an actin regulator. Here, we investigated direct effects of Profilin on microtubule dynamics, and whether ALS-linked mutations in PFN1 disrupt such functions. We found that human, fly, and yeast Profilin homologs all directly enhance microtubule growth rate by several-fold in vitro. Microtubule stimulatory effects were unaffected by mutations in the canonical actin- or poly-proline-binding sites of Profilin. Instead, microtubule activities depended on specific surface residues on Profilin mutated in ALS patients. Further, microtubule effects were attenuated by increasing concentrations of actin monomers, suggesting competition between actin and microtubules for binding Profilin. Consistent with these biochemical observations, a two-fold increase in the expression level of wildtype PFN1, but not the ALS-linked PFN1 mutants, increased microtubule growth rates in cells. Together, these results demonstrate that Profilin directly enhances the growth rate of microtubules. Further, they suggest that ALS-linked mutations in PFN1 may perturb cellular microtubule dynamics, and/or the coordination between the actin and microtubule cytoskeletons, leading to motor neuron degeneration.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis

2017

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Profilin as a dual regulator of actin and microtubule dynamics

Pinto‐Costa

Sousa

2019

Cytoskeleton

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Although originally identified as G‐actin sequestering proteins, profilins are emerging as critical regulators of actin dynamics, capable of interacting with multiple acting binding proteins, and being able to link membrane lipids to cytoskeleton components. Recently, in addition to its actin, poly‐proline, and phosphatidylinositol binding domains, profilin has been shown to contain residues specialized in microtubule binding. Here we will discuss in a critical perspective the emerging body of data supporting that profilins are central mediators of actin microfilament and microtubule interaction. We will also address the unanswered questions in the field, including the nature of the interaction of profilin with microtubules, and its effect on microtubule dynamics. These recent discoveries deepen our understanding on how different cytoskeleton components are integrated within cells.

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Using ALS to understand profilin 1's diverse roles in cellular physiology

Lindamood,

Liu,

Read

et al. 2024

Cytoskeleton

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Profilin is an actin monomer‐binding protein whose role in actin polymerization has been studied for nearly 50 years. While its principal biochemical features are now well understood, many questions remain about how profilin controls diverse processes within the cell. Dysregulation of profilin has been implicated in a broad range of human diseases, including neurodegeneration, inflammatory disorders, cardiac disease, and cancer. For example, mutations in the profilin 1 gene (PFN1) can cause amyotrophic lateral sclerosis (ALS), although the precise mechanisms that drive neurodegeneration remain unclear. While initial work suggested proteostasis and actin cytoskeleton defects as the main pathological pathways, multiple novel functions for PFN1 have since been discovered that may also contribute to ALS, including the regulation of nucleocytoplasmic transport, stress granules, mitochondria, and microtubules. Here, we will review these newly discovered roles for PFN1, speculate on their contribution to ALS, and discuss how defects in actin can contribute to these processes. By understanding profilin 1's involvement in ALS pathogenesis, we hope to gain insight into this functionally complex protein with significant influence over cellular physiology.

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Profilin connects actin assembly with microtubule dynamics

Abstract: Profilin is a well-known regulator of actin filament formation. It indirectly associates with microtubules and influences their growth rate. Formins are the linker molecules, and the turnover of the actin microfilament system balances profilin association with the microtubules.

Cited by 52 publications

References 79 publications

Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis

Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis

Profilin as a dual regulator of actin and microtubule dynamics

Using ALS to understand profilin 1's diverse roles in cellular physiology

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