Equine lentivirus counteracts SAMHD1 restriction by Rev-mediated degradation of SAMHD1 via the BECN1-dependent lysosomal pathway
AUTOPHAGY
Authors: Ren, Huiling; Yin, Xin; Su, Chao; Guo, Miaomiao; Wang, Xue-Feng; Na, Lei; Lin, Yuezhi; Wang, Xiaojun
Abstract
The innate immune restriction factor SAMHD1 can inhibit diverse viruses in myeloid cells. Mechanistically, SAMHD1 inhibits lentiviral replication including HIV-1 by depleting the nucleotide pool to interfere with their reverse transcription. Equine infectious anemia virus (EIAV) is an ancient lentivirus that preferentially attacks macrophages. However, the mechanism by which EIAV successfully establishes infection in macrophages with functional SAMHD1 remains unclear. Here, we demonstrate that while equine SAMDH1 can limit EIAV replication in equine macrophages at the reverse transcription stage, the antiviral effect is counteracted by the well-known transcriptional regulator Rev, which downregulates equine SAMHD1 through the lysosomal pathway. Remarkably, Rev hijacks BECN1 (beclin 1) and PIK3C3 to mediate SAMHD1 degradation in a canonical macroautophagy/autophagy-independent pathway. Our study illustrates that equine lentiviral Rev possesses important functions in evading cellular innate immunity in addition to its RNA regulatory function, and may provide new insights into the co-evolutionary arms race between SAMHD1 and lentiviruses.
Interplay of hydrophobic and hydrophilic interactions in sequence-dependent cell penetration of spontaneous membrane-translocating peptides revealed by bias-exchange metadynamics simulations
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Authors: Cao, Zanxia; Liu, Lei; Hu, Guodong; Bian, Yunqiang; Li, Haiyan; Wang, Jihua; Zhou, Yaoqi
Abstract
Spontaneous Membrane Translocating Peptides (SMTPs) can translocate silently across the bilayer and, thus, have the best potential to improve the delivery of therapeutic molecules to cells without toxicity. However, how their translocation mechanisms are affected by a specific peptide sequence remains poorly understood. Here, bias-exchange metadynamics simulations were employed to investigate the translocation mechanisms of five SMTPs with the same composition of amino acids (LLRLR, LRLLR, LLLRR, RLLLR, and LRLRL). Simulation results yield sequence-dependent free energy barrier using the FESs along the z-directional distance. An in-depth analysis of sequence-dependent interactions in different regions of the bilayers indicates that the free-energy barrier height of a specific sequence is resulted from the accessibility balance of isolated or clustered hydrophobic residues (L) and hydrophilic residues (R) that leads to different levels of resistance for moving of a peptide into the hydrophobic center of the membrane. At the maximal of the free-energy barrier, all peptides have a conformation parallel to the membrane surface with the barrier height determined by their affinity to the hydrophobic region. The appropriate bilayer perturbation and GDM(+) pairing are beneficial for peptide translocation. These results provide an improved microscopic understanding of how peptide sequence influences the translocation efficiency and mechanism.
COA
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