STIP1/HOP Regulates the Actin Cytoskeleton through Interactions with Actin and Changes in Actin-Binding Proteins Cofilin and Profilin

Abstract

Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.

The Hsp70–Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration

“…This indicated that most of the intracellular Hop molecules are complexed with Hsp70 and Hsp90 [28]. However, evidence has been emerging that intracellular Hop can interact with other proteins independently of its binding to either Hsp70 or Hsp90 or both [59][60][61][62][63][64].…”

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

“…STI1-PRPC interactions are neuroprotective, protecting cells against apoptosis (Lopes et al, 2005;Zanata et al, 2002). Though the exact signaling mechanism is unknown, STI1 is important in maintaining correct actin dynamics (Beckley et al, 2020). Critically, Ostapchenko and colleagues show upregulation of cortical STI1 in an AD mouse model and the brains of AD sufferers.…”

“…influx via α7NicR promoting neuronal survival and differentiation. (Beckley et al, 2020;Linden, 2017;See Miranzadeh Mahabadi and Taghibiglou, 2020;Ostapchenko et al, 2013;Santos et al, 2013)…”

Prion Protein at the Leading Edge: Its Role in Cell Motility

“…Although STI1 is a known PrP C partner, the PrP C –STI1 complex has not been closely studied in the context of cell motility, despite evidence of its importance. Murine STI1 has been shown to strongly and specifically bind F-actin through its TPR2A and TPR2B domains, which interestingly are also PrP C binding sites [ 62 ]. Given the high degree of evolutionary conservation of PrP C and STI1, their wide distribution in different cell types and the data gathered here, the PrP C –STI1 complex may regulate processes associated with cell migration, thus requiring further investigation.…”

“…While preferential localization of PrP C in specific membrane microdomains favors its interaction with Fyn, supporting proper axon guidance [ 51 ], actin cytoskeleton reorganization [ 37 ], and N-cadherin transport in the plasma membrane [ 53 ], PrP C is also involved in the promotion of metastasis through Fyn activation [ 116 ]. Additionally, F-actin and PrP C bind STI1 through the same domain [ 62 ], and several lines of evidence point to the promotion of neuroprotection through PrP C –STI1 interaction [ 59 , 60 , 61 ], while the same interaction was associated to cancer cell migration and invasion through ERK1/2 activation [ 93 ]. These are some of the examples of physiological PrP C -binding preferences that cancer cells might hijack to improve tumor maintenance, invasion and migration.…”