Theileria highjacks JNK2 into a complex with the macroschizont GPI (GlycosylPhosphatidylInositol)-anchored surface protein p104

Abstract

Constitutive c‐Jun N‐terminal kinase (JNK) activity characterizes bovine T and B cells infected with Theileria parva, and B cells and macrophages infected with Theileria annulata. Here, we show that T. annulata infection of macrophages manipulates JNK activation by recruiting JNK2 and not JNK1 to the parasite surface, whereas JNK1 is found predominantly in the host cell nucleus. At the parasite's surface, JNK2 forms a complex with p104, a GPI‐(GlycosylPhosphatidylInositol)‐anchor T. annulata plasma membrane protein. Sequestration of JNK2 depended on Protein Kinase‐A (PKA)‐mediated phosphorylation of a JNK‐binding motif common to T. parva and a cell penetrating peptide harbouring the conserved p104 JNK‐binding motif competitively ablated binding, whereupon liberated JNK2 became ubiquitinated and degraded. Cytosolic sequestration of JNK2 suppressed small mitochondrial ARF‐mediated autophagy, whereas it sustained nuclear JNK1 levels, c‐Jun phosphorylation, and matrigel traversal. Therefore, T. annulata sequestration of JNK2 contributes to both survival and dissemination of Theileria‐transformed macrophages.

The unicellular eukaryotic parasite Toxoplasma gondii hijacks the migration machinery of mononuclear phagocytes to promote its dissemination

“…Thus, infecting immune cells and hijacking or even exacerbating their migratory properties promotes coccidian parasite dissemination. Similarly, the apicomplexan Theileria hijacks MAPK signalling and conveys immortalisation and altered migratory properties to infected leukocytes (Tretina et al, 2015;Latre De Late et al, 2019).…”

Theileria’s Strategies and Effector Mechanisms for Host Cell Transformation: From Invasion to Immortalization

“…Theileria modulates the host phenotype not only by secreting proteins to the host cytoplasm or nucleus, but also by recruiting host signaling molecules to its surface. Some interesting examples are the recruitment and activation of IKK signalosomes at the PPM, leading to anti-apoptotic NF-kB signaling (Heussler et al, 2002), or the p104-mediated binding of JNK2 to the parasite surface that might contribute to c-Jun activation (Latré De Laté et al, 2019). However, the details of the mechanisms by which JNK2 and IKK are sequestered at the PPM have not been fully uncovered.…”

“…Treatment with the (S > A) mutant peptide as well as irrelevant peptides served as an important control and exerted no effect on matrigel traversal. These data point to a role for p104 in sequestering JNK2 at the parasite surface which might contribute to promoting the survival of the transformed cell by stabilizing c-Jun in the nucleus (Latré De Laté et al, 2019). Secretion of a parasite prolyl isomerase, TaPIN1 (TA18945), has also been implicated in stabilizing c-Jun levels and thus promoting Theileria-induced transformation (Marsolier et al, 2015), and will be discussed in the next section.…”

“…Loss of jnk2 in mouse cells leads to an increase in cell proliferation, while loss of jnk1 leads to decreased proliferation (Bode and Dong, 2007;Latré De Laté et al, 2019). In T. annulata infected macrophages, bovine JNK1 was detected in both the nucleus and cytoplasm of the host, while JNK2 is localized mainly in the cytoplasm and accumulates at the membrane of the schizont (Latré De Laté et al, 2019). T. annulata p104 contains three putative JNK-binding motifs and co-precipitates with JNK following immunoprecipitation with anti-pan JNK antibodies.…”

Theileria secretes proteins to subvert its host leukocyte

“…The syncytium is associated with the Microtubule Organizing Centre (MTOC) located to one side of the large nucleus of the infected and parasite transformed leukocyte. Ta-p104 is also known as a T. parva microneme-rhoptry antigen and is a secreted T. annulata protein anchored to the schizont plasma membrane where it binds to leukocyte EB1 (Wodds et al, 2013b) and JNK2 kinase (Latré De Laté et al, 2019). Scale bar: 10 μm.…”