McInally, S. | bioRxiv Science

bioRxiv2026

Cofilin controls actin network identity by sorting actin binding proteins to distinct cytoskeletal structures

Proper cell physiology requires the co-assembly of multiple actin cytoskeletal networks that are tailored for specific functions. To maintain and promote the different functions of these networks, cells decorate them with distinct types of actin binding proteins (ABPs). While various models have been proposed to explain this selective sorting of ABPs, the role of actin disassembly factors is less well understood. Here, we used inducible CRISPR interference and quantitative live-cell imaging to test how disassembly factors control the ABP composition of different networks. We found that knockdown of cofilin (Cof1), a potent and highly conserved disassembly factor, disrupts the size, organization, and ABP composition of actin networks. Specifically, defects in Cof1-mediated disassembly disrupt intracellular transport due to the assembly of overgrown and disordered branched actin networks that are inappropriately decorated by tropomyosin (Tpm1). Contrary to prevailing models of ABP sorting, these networks are co-decorated by Tpm1 and fimbrin (Sac6), and their assembly is independent of formin activity. Instead, our findings support a model wherein failure to maintain the proper architecture of branched actin networks drives mis-localization of network-specific ABPs. Together, this work demonstrates that actin disassembly factors play a critical role in maintaining cytoskeletal structure and function to regulate ABP sorting across distinct networks.

Cell Biology↗

bioRxiv2019

Low Replication Capacity Virus Is Preferentially Transmitted In Mother-To-Child-Transmission But Not In Adult-To-Adult-Transmission Of HIV-1

Previous studies of the transmitted/founder virus compared to viral quasispecies in the donor have yielded conflicting results. In heterosexual adult-to-adult transmission (ATAT), the viral replicative capacity (VRC) of transmitted virus is reportedly either similar to, or somewhat higher than, that of donor virus, whilst transmitted virus in mother-to-child transmission (MTCT) has a significantly lower VRC than that of maternal virus. These discrepancies may be explained by the different methodologies used in these studies, or they may reflect true differences in the transmission bottleneck. To resolve this question, we here use the same methodology to compare transmitted versus donor virus in MTCT and ATAT. We show that, in a South African mother-child cohort, infant virus samples obtained at 1-2 days after birth had VRC significantly lower than in the mothers (p=0.0003). By contrast, in Zambian ATAT transmission pairs, VRC of transmitted virus was similar to or somewhat higher than donor virus (p=ns). The VRC of virus transmitted to the recipient, compared to that in the donor, was significantly lower in MTCT versus heterosexual ATAT (p=0.01). These studies demonstrate that fundamental differences exist between the viruses transmitted via the MTCT and ATAT bottlenecks that are not explained by methodological factors. This result is of importance since transmission of low replicative capacity virus results in low immune activation and a small viral reservoir, and therefore the preferential transmission of low fitness viruses in MTCT might be expected to increase cure potential in in utero infected infants and children.\n\nIMPORTANCEUnderstanding the factors determining which viruses are preferentially transmitted in HIV infection is critical to the development of new, effective strategies to prevent transmission. Despite this, much remains unknown in this respect, both with regard to adult-to-adult transmission (ATAT) but especially with respect to mother-to-child transmission (MTCT). The finding here that fundamental differences exist in the genetic bottleneck of HIV transmission between heterosexual ATAT and MTCT is an important initial step to help define the viral mechanisms contributing to transmission in each case. In addition, we show that viruses of low viral replicative capacity are preferentially transmitted in MTCT. This suggests the possibility that a window of opportunity exists following in utero infection in which early anti-viral intervention not only reduces the size and diversity of the viral reservoir, but additionally maintains a reservoir comprising low viral replicative capacity HIV. Low replicative capacity of transmitted virus has previously been shown to result in low immune activation and low proviral DNA load in central memory cells, factors likely to be directly relevant to increasing cure potential in HIV-infected infants and children.

immunology↗