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Autophagy is a vital cellular pathway in eukaryotic cells, including neurons, where it plays significant roles in neurodevelopment and maintenance. A crucial step in autophagy is the formation of the class III phosphatidylinositol 3-kinase complex 1 (PI3KC3-C1), which is essential for initiating autophagosome biogenesis. Beclin 1 is the key component of PI3KC3-C1, and its interactors have been reported to affect autophagy. The brain-enriched adaptor protein FE65 has been shown to interact with Alzheimer’s disease amyloid precursor protein (APP) to alter the processing of APP. Additionally, FE65 has been implicated in various cellular pathways, including autophagy. We demonstrate here that FE65 positively regulates autophagy. FE65, through its C-terminus, has been shown to interact with Beclin 1. Notably, the overexpression of FE65 enhances Beclin 1-mediated autophagy, whereas this process is attenuated in FE65 knockout cells. Moreover, the stimulatory effect of FE65 on Beclin 1-mediated autophagy is diminished by an FE65 C-terminus deletion mutant that disrupts the FE65–Beclin 1 interaction. Lastly, we have found that the FE65-Beclin 1 interaction modulates the kinase activity of the PI3KC3-C1 complex. Together, we have identified FE65 as a novel Beclin 1 interactor, and this interaction potentiates autophagy.

Objective: RAC1 aberrations in head and neck squamous cell carcinoma (HNSCC) remain clinically inactionable today. Methods: Here, we investigated the clinical significance and potential druggability of RAC1 genomic aberrations in HNSCC. Results: Notably, HPV(−)HNSCC patients bearing the unique HNSCC-prevalent RAC1-A159V hotspot mutation, P29S hotspot and G-box domain mutations, and RAC1 copy number increases all displayed dismal overall survival (TCGA-HNSCC). Here, we demonstrated that all five HNSCC patient-relevant RAC1 aberrations tested (A159V and P29S hotspot mutations, K116N, G15S, and N39S) could significantly drive HNSCC tumoroid growth and/invasion, with A159V, P29S, and K116N mutants being the most potent drivers. Interestingly, transcriptomics analyses revealed that RAC1 mutations and copy increase could both drive PI3K pathway activation, with the A159V mutant associated with the prominent intra-tumoral upregulation of phospho-RPS6(Ser235/236) in patient tumors. Importantly, proof-of-principle Rac targeting with EHop-016 resulted in remarkable antitumor activity in vivo against RAC1-A159V-mutated and RAC1-amplified HNSCC patient-derived xenografts (PDXs) and/engineered models. Lastly, melanoma and endometrial xenograft models bearing endogenous RAC1-amplification and RAC1-A159V mutation were also sensitive to EHop-016 targeting. Conclusions: In principle, RAC1 genomic aberrations in HNSCC can be potentially harnessed for precision drugging.

Activating the intrinsic pathways for neurite outgrowth could potentially lead to axon regeneration in CNS neurons (He and Jin, 2016). [...]understanding the regulatory mechanisms of neurite outgrowth would not only advance our knowledge in brain development but also provide insights into methods of inducing neurite re-outgrowth after brain injuries and in the aftermath of neurodegenerative diseases. [...]a study shows that the selective activation of Rac1 could enhance neuronal survival and axonal regeneration while preventing dendrite degeneration in retinal ganglion cells after crush injuries. [...]our recent finding provides the first source of evidence for the aforementioned proposal as the interaction of FE65 and ELMO1 EAD relieves the ELMO1 autoinhibitory conformation and stimulates Rac1 and neurite outgrowth in primary rat cortical neurons (Li et al., 2018) [Figure 1]. [...]the LDL receptor-related protein 1 (LRP1) agonist increases neurite outgrowth in dorsal root ganglion neurons.

Autophagy is a highly conserved catabolic mechanism by which unnecessary or dysfunctional cellular components are removed. The dysregulation of autophagy has been implicated in various neurodegenerative diseases, including Alzheimer’s disease (AD). Understanding the molecular mechanism(s)/molecules that influence autophagy may provide important insights into developing therapeutic strategies against AD and other neurodegenerative disorders. Engulfment adaptor phosphotyrosine-binding domain-containing protein 1 (GULP1) is an adaptor that interacts with amyloid precursor protein (APP) to promote amyloid-β peptide production via an unidentified mechanism. Emerging evidence suggests that GULP1 has a role in autophagy. Here, we show that GULP1 is involved in autophagy through an interaction with autophagy-related 14 (ATG14), which is a regulator of autophagosome formation. GULP1 potentiated the stimulatory effect of ATG14 on autophagy by modulating class III phosphatidylinositol 3-kinase complex 1 (PI3KC3-C1) activity. The effect of GULP1 is attenuated by a GULP1 mutation (GULP1m) that disrupts the GULP1–ATG14 interaction. Conversely, PI3KC3-C1 activity is enhanced in cells expressing APP but not in those expressing an APP mutant that does not bind GULP1, which suggests a role of GULP1–APP in regulating PI3KC3-C1 activity. Notably, GULP1 facilitates the targeting of ATG14 to the endoplasmic reticulum (ER). Moreover, the levels of both ATG14 and APP are elevated in the autophagic vacuoles (AVs) of cells expressing GULP1, but not in those expressing GULP1m. APP processing is markedly enhanced in cells co-expressing GULP1 and ATG14. Hence, GULP1 alters APP processing by promoting the entry of APP into AVs. In summary, we unveil a novel role of GULP1 in enhancing the targeting of ATG14 to the ER to stimulate autophagy and, consequently, APP processing.