BACKGROUND: The P/C mRNA of Sendai virus (SeV), a prototypic member of the family Paramyxoviridae in the Mononegavirales superfamily comprising a large number of nonsegmented negative strand RNA viruses, encodes a nested set of accessory proteins, C', C, Y1 and Y2, referred to collectively as C proteins, initiating, respectively, at ACG/81 and AUGs/114, 183, 201 in the +1 frame relative to the ORF of phospho (P) protein, the smaller subunit of RNA polymerase. Among them, C is the major species expressed in infected cells at a molar ratio which is several-fold higher than the other three. However, their function has remained an enigma. It has not even been established whether or not the C proteins are essential for viral replication. Many other viruses in Mononegavirales encode C-like proteins, but their roles also remain to be defined. RESULTS: By taking advantage of a recently developed reverse genetics system to recover infectious SeV from cDNA, we created mutants in which C protein frames were variously silenced. C/C'(-) viruses which did not express C and C', but did express Y1 and Y2, were severely attenuated in replication in tissue culture cells of various species and tissues, as well as in embryonated chicken eggs. More notably, they were almost totally incapable of growing productively in--and hence nonpathogenic for mice--the natural host. Both gene expression and genome replication appeared to be impaired in C/C'(-) viruses. Additionally silencing the Y1 and Y2 expression was also possible, and a critically impaired but viable clone, the 4C(-) virus, was isolated which expressed none of the four C proteins. CONCLUSION: SeV C proteins are categorically nonessential gene products, but greatly contribute to full replication capability in vitro and are indispensable for in vivo multiplication and pathogenesis. This study represents the first comprehensive functional assessment of the accessary C protein for Mononegavirales.

This article has been cited by other articles:

				K. Takeuchi, T. Komatsu, Y. Kitagawa, K. Sada, and B. Gotoh Sendai Virus C Protein Plays a Role in Restricting PKR Activation by Limiting the Generation of Intracellular Double-Stranded RNA J. Virol., October 15, 2008; 82(20): 10102 - 10110. [Abstract] [Full Text] [PDF]

				E. J. Bartlett, A.-M. Cruz, J. Esker, A. Castano, H. Schomacker, S. R. Surman, M. Hennessey, J. Boonyaratanakornkit, R. J. Pickles, P. L. Collins, et al. Human Parainfluenza Virus Type 1 C Proteins Are Nonessential Proteins That Inhibit the Host Interferon and Apoptotic Responses and Are Required for Efficient Replication in Nonhuman Primates J. Virol., September 15, 2008; 82(18): 8965 - 8977. [Abstract] [Full Text] [PDF]

				A. Kato, K. Kiyotani, T. Kubota, T. Yoshida, M. Tashiro, and Y. Nagai Importance of the Anti-Interferon Capacity of Sendai Virus C Protein for Pathogenicity in Mice J. Virol., April 1, 2007; 81(7): 3264 - 3271. [Abstract] [Full Text] [PDF]

				J.-B. Marq, A. Brini, D. Kolakofsky, and D. Garcin Targeting of the Sendai Virus C Protein to the Plasma Membrane via a Peptide-Only Membrane Anchor J. Virol., April 1, 2007; 81(7): 3187 - 3197. [Abstract] [Full Text] [PDF]

				G. Mottet-Osman, F. Iseni, T. Pelet, M. Wiznerowicz, D. Garcin, and L. Roux Suppression of the Sendai Virus M Protein through a Novel Short Interfering RNA Approach Inhibits Viral Particle Production but Does Not Affect Viral RNA Synthesis J. Virol., March 15, 2007; 81(6): 2861 - 2868. [Abstract] [Full Text] [PDF]

				T. Sakaguchi, A. Kato, F. Sugahara, Y. Shimazu, M. Inoue, K. Kiyotani, Y. Nagai, and T. Yoshida AIP1/Alix Is a Binding Partner of Sendai Virus C Protein and Facilitates Virus Budding J. Virol., July 15, 2005; 79(14): 8933 - 8941. [Abstract] [Full Text] [PDF]

				K. Takeuchi, M. Takeda, N. Miyajima, Y. Ami, N. Nagata, Y. Suzaki, J. Shahnewaz, S.-i. Kadota, and K. Nagata Stringent Requirement for the C Protein of Wild-Type Measles Virus for Growth both In Vitro and in Macaques J. Virol., June 15, 2005; 79(12): 7838 - 7844. [Abstract] [Full Text] [PDF]

				A. G. Malur, S. Chattopadhyay, R. K. Maitra, and A. K. Banerjee Inhibition of STAT 1 Phosphorylation by Human Parainfluenza Virus Type 3 C Protein J. Virol., June 15, 2005; 79(12): 7877 - 7882. [Abstract] [Full Text] [PDF]

				A. Kato, C. Cortese-Grogan, S. A. Moyer, F. Sugahara, T. Sakaguchi, T. Kubota, N. Otsuki, M. Kohase, M. Tashiro, and Y. Nagai Characterization of the Amino Acid Residues of Sendai Virus C Protein That Are Critically Involved in Its Interferon Antagonism and RNA Synthesis Down-Regulation J. Virol., July 15, 2004; 78(14): 7443 - 7454. [Abstract] [Full Text] [PDF]

				D. Garcin, J.-B. Marq, S. Goodbourn, and D. Kolakofsky The Amino-Terminal Extensions of the Longer Sendai Virus C Proteins Modulate pY701-Stat1 and Bulk Stat1 Levels Independently of Interferon Signaling J. Virol., February 15, 2003; 77(4): 2321 - 2329. [Abstract] [Full Text] [PDF]

				G. Neumann, M. A. Whitt, and Y. Kawaoka A decade after the generation of a negative-sense RNA virus from cloned cDNA - what have we learned? J. Gen. Virol., November 1, 2002; 83(11): 2635 - 2662. [Abstract] [Full Text] [PDF]

				D. Garcin, J. Curran, M. Itoh, and D. Kolakofsky Longer and Shorter Forms of Sendai Virus C Proteins Play Different Roles in Modulating the Cellular Antiviral Response J. Virol., August 1, 2001; 75(15): 6800 - 6807. [Abstract] [Full Text]

				C. L. Parks, R. A. Lerch, P. Walpita, H.-P. Wang, M. S. Sidhu, and S. A. Udem Comparison of Predicted Amino Acid Sequences of Measles Virus Strains in the Edmonston Vaccine Lineage J. Virol., January 15, 2001; 75(2): 910 - 920. [Abstract] [Full Text]

				C. Huang, K. Kiyotani, Y. Fujii, N. Fukuhara, A. Kato, Y. Nagai, T. Yoshida, and T. Sakaguchi Involvement of the Zinc-Binding Capacity of Sendai Virus V Protein in Viral Pathogenesis J. Virol., September 1, 2000; 74(17): 7834 - 7841. [Abstract] [Full Text]

				M. D. Baron and T. Barrett Rinderpest Viruses Lacking the C and V Proteins Show Specific Defects in Growth and Transcription of Viral RNAs J. Virol., March 15, 2000; 74(6): 2603 - 2611. [Abstract] [Full Text]

				H. Jin, X. Cheng, H. Z. Y. Zhou, S. Li, and A. Seddiqui Respiratory Syncytial Virus That Lacks Open Reading Frame 2 of the M2 Gene (M2-2) Has Altered Growth Characteristics and Is Attenuated in Rodents J. Virol., January 1, 2000; 74(1): 74 - 82. [Abstract] [Full Text]

				A. Kato, K. Kiyotani, M. K. Hasan, T. Shioda, Y. Sakai, T. Yoshida, and Y. Nagai Sendai Virus Gene Start Signals Are Not Equivalent in Reinitiation Capacity: Moderation at the Fusion Protein Gene J. Virol., November 1, 1999; 73(11): 9237 - 9246. [Abstract] [Full Text] [PDF]

				A. Bermingham and P. L. Collins The M2-2 protein of human respiratory syncytial virus is a regulatory factor involved in the balance between RNA replication and transcription PNAS, September 28, 1999; 96(20): 11259 - 11264. [Abstract] [Full Text] [PDF]

				P. Latorre, T. Cadd, M. Itoh, J. Curran, and D. Kolakofsky The Various Sendai Virus C Proteins Are Not Functionally Equivalent and Exert both Positive and Negative Effects on Viral RNA Accumulation during the Course of Infection J. Virol., July 1, 1998; 72(7): 5984 - 5993. [Abstract] [Full Text] [PDF]