Seongmin Yoon, Konstantin Bogdanov and David Wallach
Department of Biomolecular Sciences, The Weizmann Institute of Science, 7610001 Rehovot, Israel
Signalling molecules targeted by the TNF receptor family serve mainly for immune defense. As such, each is endowed with a wide range of different functions that has kept expanding during the long host-pathogen tug of war.
Much has been learnt already about the multiplicity of functions of proximal signalling enzymes that the receptors activate, and of the wide range of regulatory mechanisms that coordinate them. Emerging knowledge reveals similar complexity in the function of the effector proteins that the receptors activate.
The pseudokinase MLKL was initially discovered as the effector protein in necroptosis - a programmed necrotic form of death that TNF can trigger, but is now known also to serve other functions. Alongside the emerging awareness of the heterogeneity of functions of MLKL there is growing knowledge of heterogeneity of subcellular sites of action of this protein, and of regulatory mechanisms that coordinate these differing functions. We previously reported that, apart from its translocation to the cellular membrane, where it exerts its cytotoxic effect, MLKL also associates with endosomal membranes (1). We shall now show that the latter association is dictated by ubiquitination of specific lysine residues at the N-terminal four-helix bundle (HeLo) domain of MLKL. We shall further show that, upon its association with the endosomes, MLKL facilitates the transport of intracellular pathogens to the lysosomes and their destruction there, prior to the death of the host cell.
Unlike apoptosis, in which the dying cell is taken up intact by phagocytic cells, necrotic death is characterized by rupture of the cell membrane at the time of death. The targeting of intracellular pathogens to the lysosomes before the actual occurrence necroptotitc cell death apparently serves as safeguard against the release of live pathogens from the dying cell.
1. Yoon S, Kovalenko A et al (2017) Immunity 47:51 (doi: 10.1016/j.immuni.2017.06.001)

Seongmin Yoon, Konstantin Bogdanov and David Wallach
Department of Biomolecular Sciences, The Weizmann Institute of Science, 7610001 Rehovot, Israel
Signalling molecules targeted by the TNF receptor family serve mainly for immune defense. As such, each is endowed with a wide range of different functions that has kept expanding during the long host-pathogen tug of war.
Much has been learnt already about the multiplicity of functions of proximal signalling enzymes that the receptors activate, and of the wide range of regulatory mechanisms that coordinate them. Emerging knowledge reveals similar complexity in the function of the effector proteins that the receptors activate.
The pseudokinase MLKL was initially discovered as the effector protein in necroptosis - a programmed necrotic form of death that TNF can trigger, but is now known also to serve other functions. Alongside the emerging awareness of the heterogeneity of functions of MLKL there is growing knowledge of heterogeneity of subcellular sites of action of this protein, and of regulatory mechanisms that coordinate these differing functions. We previously reported that, apart from its translocation to the cellular membrane, where it exerts its cytotoxic effect, MLKL also associates with endosomal membranes (1). We shall now show that the latter association is dictated by ubiquitination of specific lysine residues at the N-terminal four-helix bundle (HeLo) domain of MLKL. We shall further show that, upon its association with the endosomes, MLKL facilitates the transport of intracellular pathogens to the lysosomes and their destruction there, prior to the death of the host cell.
Unlike apoptosis, in which the dying cell is taken up intact by phagocytic cells, necrotic death is characterized by rupture of the cell membrane at the time of death. The targeting of intracellular pathogens to the lysosomes before the actual occurrence necroptotitc cell death apparently serves as safeguard against the release of **live pathogens from the dying cell.**
1. Yoon S, Kovalenko A et al (2017) _Immunity_ 47:51 (doi: 10.1016/j.immuni.2017.06.001)

Coordinating immune-defence functions of MLKL: endosomal targeting of MLKL by site specific ubiquitination facilitates lysosomal destruction of intracellular pathogenes

Exploring the intricacies of host-pathogen communication is vital in order to understand why
some microbes persist within a host, while others are effectively cleared. As such,
host-pathogen communication is an urgent area of research underpinning human health
and disease, especially given the emerging concerns of antibiotic resistance.
Understanding host-pathogen pathways requires intricate knowledge in the fields of both
microbiology and immunology.

Living in a world of specialists, where scientists sometimes invest their whole career
studying one organism, a specific pathway or a protein, multidisciplinary discussions of
host-pathogen interactions are highly needed. This international conference will provide
such a forum for scientific exchange at the highest level, between scientists from different
research areas related to host-pathogen interactions, with the aim to trigger fruitful
collaborations addressing the urgent questions in the field.

This meeting has an additional special focus of bringing researchers from Ireland, Denmark
and Israel together to learn about cutting edge biology and form new collaborations.
Thus, the conference will be a showcase for the exciting and original research emanating
from these three small but innovative countries.

Host-Pathogen Communication (HPC) 2021

Awards & close

Initiation and Regulation of Innate Immunity