Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration

Ah-Lai Law,Anett Jandke,Stefania Marcotti,James A Levitt,Fuad Mosis,Shamsinar Jalal,Simon P Poland,Lawrence Yolland,Tommy Pallett,Robert Köchl,Simon Brayford,Giordano Pula,Simon M Ameer-Beg,Matthias Krause,Maia Rowe-Sampson,Ahmad Guni,Brian Marc Stramer

doi:10.1038/s41467-021-25916-6

Abstract

Cell migration is important for development and its aberrant regulation contributes to many diseases. The Scar/WAVE complex is essential for Arp2/3 mediated lamellipodia formation during mesenchymal cell migration and several coinciding signals activate it. However, so far, no direct negative regulators are known. Here we identify Nance-Horan Syndrome-like 1 protein (NHSL1) as a direct binding partner of the Scar/WAVE complex, which co-localise at protruding lamellipodia. This interaction is mediated by the Abi SH3 domain and two binding sites in NHSL1. Furthermore, active Rac binds to NHSL1 at two regions that mediate leading edge targeting of NHSL1. Surprisingly, NHSL1 inhibits cell migration through its interaction with the Scar/WAVE complex. Mechanistically, NHSL1 may reduce cell migration efficiency by impeding Arp2/3 activity, as measured in cells using a Arp2/3 FRET-FLIM biosensor, resulting in reduced F-actin density of lamellipodia, and consequently impairing the stability of lamellipodia protrusions.

Highlights

Cell migration is important for development and its aberrant regulation contributes to many diseases
We found that FRET efficiency and Arp2/3 activity was significantly increased in both Nance-Horan Syndrome-like 1 protein (NHSL1) CRISPR 2 and 21 cell lines compared to control B16-F1 cells (Fig. 7d–f and Supplementary Fig. 14a–f)
The Scar/WAVE complex, which is activated by several signals including Rac, is essential for lamellipodia formation and promotes mesenchymal cell migration[2]

Summary

Introduction

Cell migration is important for development and its aberrant regulation contributes to many diseases. We identify Nance-Horan Syndrome-like 1 protein (NHSL1) as a direct binding partner of the Scar/WAVE complex, which co-localise at protruding lamellipodia This interaction is mediated by the Abi SH3 domain and two binding sites in NHSL1. We postulate that the Scar/WAVE complex needs to be negatively regulated at the leading edge to tightly control lamellipodial protrusion dynamics and cell steering It is not known how the Scar/WAVE complex is directly inhibited at the leading edge. We identify NHSL1 (Nance–Horan Syndrome-like 1) protein as a negative regulator of cell migration and we find that this is mediated by its interaction with the Scar/WAVE complex. Our data suggest that NHSL1 negatively regulates the Scar/WAVE complex, and reduces Arp2/3 activity, to control lamellipodia stability and cell migration efficiency

Methods

Results

Conclusion