English: Replication cycle of phleboviruses. (A) Cellular attachment of phleboviruses is driven by glycoprotein interactions with host cell factors such as dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), heparan sulfate (HS), or non-muscle myosin heavy chain IIA (NMMHC-IIA). The binding to DC-SIGN and so far unknown entry factors induces uptake via caveolin-1-mediated endocytosis (CavME) (as for Rift Valley fever virus, RVFV) or incompletely defined clathrin-independent endocytic (CIE) mechanisms (as for Uukuniemi virus, UUKV). Ribonuclease kappa (RNaseK) promotes the internalization of virions by a yet unknown mechanism; (B) In late endosomes, the low pH induces the membrane fusion activity of the Gc protein. Expression of vesicle-associated membrane protein 3 (VAMP3) promotes UUKV penetration, while interferon-induced transmembrane protein (IFITM) 2 and IFITM3 inhibit the fusion of RVFV in late endosomes; (C) The fusion of viral and endosomal membranes allows release of the viral ribonucleoprotein complexes into the cytoplasm, the site of viral transcription and replication; (D) The viral glycoproteins Gn and Gc are translated at the rough endoplasmic reticulum (ER) as a precursor protein, Gn/Gc, which is cleaved by signal peptidase. The viral nucleoprotein and the viral polymerase are synthesized in the cytoplasm where they form together with newly produced genomic RNA (gRNA) ribonucleoprotein (RNP) complexes; (E) Binding immunoglobulin protein (BiP) and calnexin, two ER chaperones, are required for appropriate folding of Gn and Gc. Similarly, protein-disulfide-isomerase catalyzes Gn and Gc folding by promoting the formation of disulfide bonds, while calreticulin prevents misfolded Gn and Gc from being exported from the ER to the Golgi; (F) Correctly folded Gn/Gc heterodimers are transported into the Golgi apparatus where they associate with RNPs via the cytoplasmic tails of Gn during the budding process; (G) After budding of new virus particles into the Golgi is complete, virus-containing vesicles are transported to the plasma membrane where the virions are released by exocytosis. DC: dendritic cell; MФ: macrophage; CME: clathrin-mediated endocytosis; PDI: protein disulfide isomerase; CNX: calnexin.