Universität zu Köln

Liccardi, Gianmaria and Annibaldi, Alessandro . MLKL post-translational modifications: road signs to infection, inflammation and unknown destinations. Cell Death Differ.. LONDON: SPRINGERNATURE. ISSN 1476-5403

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Abstract

Necroptosis is a caspase-independent modality of cell death that requires the activation of the executioner MLKL. In the last ten years the field gained a substantial amount of evidence regarding its involvement in host response to pathogens, TNF-induced inflammatory diseases as well as pathogen recognition receptors (PRR)-induced inflammation. However, there are still a lot of questions that remain unanswered. While it is clear that there are specific events needed to drive MLKL activation, substantial differences between human and mouse MLKL not only highlight different evolutionary pressure, but also provide potential insights on alternative modalities of activation. While in TNF-induced necroptosis it is clear the involvement of the RIPK3 mediated phosphorylation, it still remains to be understood how certain inflammatory in vivo phenotypes are not equally rescued by either RIPK3 or MLKL loss. Moreover, the plethora of different reported phosphorylation events on MLKL, even in cells that do not express RIPK3, suggest indeed that there is more to MLKL than RIPK3-mediated activation, not only in the execution of necroptosis but perhaps in other inflammatory conditions that include IFN response. The recent discovery of MLKL ubiquitination has highlighted a new checkpoint in the regulation of MLKL activation and the somewhat conflicting evidence reported certainly require some untangling. In this review we will highlight the recent findings on MLKL activation and involvement to pathogen response with a specific focus on MLKL post-translational modifications, in particular ubiquitination. This review will highlight the outstanding main questions that have risen from the last ten years of research, trying at the same time to propose potential avenues of research.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Liccardi, Gianmaria UNSPECIFIED UNSPECIFIED UNSPECIFIED Annibaldi, Alessandro UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-660879
DOI:	10.1038/s41418-022-01061-5
Journal or Publication Title:	Cell Death Differ.
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	1476-5403
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MIXED LINEAGE KINASE; TOLL-LIKE RECEPTORS; DOMAIN-LIKE PROTEIN; CELL-DEATH; PROGRAMMED NECROSIS; PSEUDOKINASE MLKL; MEDIATED APOPTOSIS; SIGNALING COMPLEX; MOLECULAR SWITCH; DISTINCT ROLES Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66087