tetano
Editor, Senior Moderator
Microbes Infect
. 2023 Dec 20:105280.
doi: 10.1016/j.micinf.2023.105280. Online ahead of print. SP-R210 isoforms of Myosin18A modulate endosomal sorting and recognition of influenza A virus infection in macrophages
Eric Yau[SUP] 1 [/SUP], Linlin Yang[SUP] 1 [/SUP], Yan Chen[SUP] 1 [/SUP], Todd M Umstead[SUP] 1 [/SUP], Anne E Stanley[SUP] 2 [/SUP], E Scott Halstead[SUP] 3 [/SUP], Chintan K Gandhi[SUP] 1 [/SUP], John W Yewdell[SUP] 4 [/SUP], Zissis C Chroneos[SUP] 5 [/SUP]
Affiliations
Influenza A virus (IAV) infection causes acute and often lethal inflammation in the lung. The role of macrophages in this adverse inflammation is partially understood. The surfactant protein A receptor 210 (SP-R210) consists of two isoforms, a long (L) SP-R210[SUB]L[/SUB] and a short (S) SP-R210[SUB]S[/SUB] isoform encoded by alternative splicing of the myosin 18A gene. We reported that disruption of SP-R210[SUB]L[/SUB] enhances cytosolic and endosomal antiviral response pathways. Here, we report that SP-R210[SUB]L[/SUB] antagonizes type I interferon β (IFNβ), as depletion of SP-R210[SUB]L[/SUB] potentiates IFNβ secretion. SP-R210 antibodies enhance and attenuate IFNβ secretion in SP-R210[SUB]L[/SUB] replete and deficient macrophages, respectively, indicating that SP-R210 isoform stoichiometry alters macrophage function intrinsically. This reciprocal response is coupled to unopposed and restricted expression of viral genes in control and SP-R210[SUB]L[/SUB]-deficient macrophages, respectively. Human monocytic cells with sub-stoichiometric expression of SP-R210[SUB]L[/SUB] resist IAV infection, whereas alveolar macrophages with increased abundance of SP-R210[SUB]L[/SUB] permit viral gene expression similar to murine macrophages. Uptake and membrane binding studies show that lack of SP-R210 isoforms does not impair IAV binding and internalization. Lack of SP-R210[SUB]L[/SUB], however, results in macropinocytic retention of the virus that depends on both SP-R210[SUB]S[/SUB] and interferon-inducible transmembrane protein-3 (IFITM3). Mass spectrometry and Western blot analyses indicate that SP-R210 isoforms modulate differential recruitment of the Rho-family GTPase RAC1 and guanine nucleotide exchange factors. Our study suggests that SP-R210 isoforms modulate RAC-dependent macropinosomal sorting of IAV to discrete endosomal and lysosomal compartments that either permit or prevent endolysosomal escape and inflammatory sensing of viral genomes in macrophages.
Keywords: IFITM3; Influenza life-cycle; Macrophages; Myosin 18A (MYO18A); Surfactant protein A receptor 210 (SP-R210); macropinocytosis.
. 2023 Dec 20:105280.
doi: 10.1016/j.micinf.2023.105280. Online ahead of print. SP-R210 isoforms of Myosin18A modulate endosomal sorting and recognition of influenza A virus infection in macrophages
Eric Yau[SUP] 1 [/SUP], Linlin Yang[SUP] 1 [/SUP], Yan Chen[SUP] 1 [/SUP], Todd M Umstead[SUP] 1 [/SUP], Anne E Stanley[SUP] 2 [/SUP], E Scott Halstead[SUP] 3 [/SUP], Chintan K Gandhi[SUP] 1 [/SUP], John W Yewdell[SUP] 4 [/SUP], Zissis C Chroneos[SUP] 5 [/SUP]
Affiliations
- PMID: 38135024
- DOI: 10.1016/j.micinf.2023.105280
Influenza A virus (IAV) infection causes acute and often lethal inflammation in the lung. The role of macrophages in this adverse inflammation is partially understood. The surfactant protein A receptor 210 (SP-R210) consists of two isoforms, a long (L) SP-R210[SUB]L[/SUB] and a short (S) SP-R210[SUB]S[/SUB] isoform encoded by alternative splicing of the myosin 18A gene. We reported that disruption of SP-R210[SUB]L[/SUB] enhances cytosolic and endosomal antiviral response pathways. Here, we report that SP-R210[SUB]L[/SUB] antagonizes type I interferon β (IFNβ), as depletion of SP-R210[SUB]L[/SUB] potentiates IFNβ secretion. SP-R210 antibodies enhance and attenuate IFNβ secretion in SP-R210[SUB]L[/SUB] replete and deficient macrophages, respectively, indicating that SP-R210 isoform stoichiometry alters macrophage function intrinsically. This reciprocal response is coupled to unopposed and restricted expression of viral genes in control and SP-R210[SUB]L[/SUB]-deficient macrophages, respectively. Human monocytic cells with sub-stoichiometric expression of SP-R210[SUB]L[/SUB] resist IAV infection, whereas alveolar macrophages with increased abundance of SP-R210[SUB]L[/SUB] permit viral gene expression similar to murine macrophages. Uptake and membrane binding studies show that lack of SP-R210 isoforms does not impair IAV binding and internalization. Lack of SP-R210[SUB]L[/SUB], however, results in macropinocytic retention of the virus that depends on both SP-R210[SUB]S[/SUB] and interferon-inducible transmembrane protein-3 (IFITM3). Mass spectrometry and Western blot analyses indicate that SP-R210 isoforms modulate differential recruitment of the Rho-family GTPase RAC1 and guanine nucleotide exchange factors. Our study suggests that SP-R210 isoforms modulate RAC-dependent macropinosomal sorting of IAV to discrete endosomal and lysosomal compartments that either permit or prevent endolysosomal escape and inflammatory sensing of viral genomes in macrophages.
Keywords: IFITM3; Influenza life-cycle; Macrophages; Myosin 18A (MYO18A); Surfactant protein A receptor 210 (SP-R210); macropinocytosis.