A mitotically inheritable unit containing a MAP kinase module

Abstract

Prions are novel kinds of hereditary units, relying solely on proteins, that are infectious and inherited in a non-Mendelian fashion. To date, they are either based on autocatalytic modification of a 3D conformation or on autocatalytic cleavage. Here, we provide further evidence that in the filamentous fungus Podospora anserina, a MAP kinase cascade is probably able to self-activate and generate C, a hereditary unit that bears many similarities to prions and triggers cell degeneration. We show that in addition to the MAPKKK gene, both the MAPKK and MAPK genes are necessary for the propagation of C, and that overexpression of MAPK as that of MAPKKK facilitates the appearance of C. We also show that a correlation exists between the presence of C and localization of the MAPK inside nuclei. These data emphasize the resemblance between prions and a self-positively regulated cascade in terms of their transmission. This thus further expands the concept of protein-base inheritance to regulatory networks that have the ability to self-activate.epigenetic ͉ prion ͉ Podospora anserina

A Non-Mendelian MAPK-Generated Hereditary Unit Controlled by a Second MAPK Pathway inPodospora anserina

“…However, unlike classical prions based on alternate conformations of proteins, the C hereditary unit seems to rely on the "ON" state of the PaMpk1 cascade. As described for the JNK cascade of Xenopus oocytes (Bagowski and Ferrell 2001), the PaMpk1 cascade would present a positive regulatory loop whereby a component downstream of the cascade upregulates an upstream component in trans (Kicka et al 2006). Therefore, once one molecule of the pathway is activated, the activation could spread to the other nonactive molecules and lock them in the ON state.…”

“…Involvement of the PaMpk1 MAPK pathway was discovered through a traditional genetics approach, i.e., we identified mutants unable to develop CG (IDC mutants with Impaired Development of CG) and found that two of the mutated genes encode the MAPKKK and MAPKK of the cascade (Kicka and Silar 2004;Kicka et al 2006). Reverse genetics showed that the PaMpk1 MAPK gene also controls CG (Kicka et al 2006).…”

“…Reverse genetics showed that the PaMpk1 MAPK gene also controls CG (Kicka et al 2006). Here, we present a thorough analysis of the MAP kinases of P. anserina and investigate the roles of these kinases in the physiology of this fungus, especially with regard to CG.…”

“…Especially, C spreads in the cytoplasm in an infectious manner (Silar et al 1999;Kicka and Silar 2004;Kicka et al 2006). When present in dividing cells, C triggers the CG degenerative process, characterized by slower mycelium growth, higher accumulation of pigment, and female sterility.…”

“…Sustained activation of the cascade in the hyphae renewing growth results in the CG altered pattern of growth. Interestingly, other genes controlling CG appeared to be involved in the correct nuclear localization in the mycelium of PaMpk1 rather than its phosphorylation (Kicka et al 2006;JametVierny et al 2007). To date, in no other fungus was a process akin to CG detected.…”