Controlling Cell Death through Post-translational Modifications of DED Proteins

Abstract

Death-inducing signaling complex (DISC) and death effector domain (DED) filaments control extrinsic apoptosis.DED filaments comprise FADD, procaspase-8/10, and c-FLIP.Post-translational modifications (PTMs) of DED filament proteins create the additional checkpoint of apoptosis.A central role in understanding apoptosis control is in deciphering the 3D architecture of PTMs in the DED filament. Apoptosis is a form of programmed cell death, deregulation of which occurs in multiple disorders, including neurodegenerative and autoimmune diseases as well as cancer. The formation of a death-inducing signaling complex (DISC) and death effector domain (DED) filaments are critical for initiation of the extrinsic apoptotic pathway. Post-translational modifications (PTMs) of DED-containing DISC components such as FADD, procaspase-8, and c-FLIP comprise an additional level of apoptosis regulation, which is necessary to overcome the threshold for apoptosis induction. In this review we discuss the influence of PTMs of FADD, procaspase-8, and c-FLIP on DED filament assembly and cell death induction, with a focus on the 3D organization of the DED filament. Apoptosis is a form of programmed cell death, deregulation of which occurs in multiple disorders, including neurodegenerative and autoimmune diseases as well as cancer. The formation of a death-inducing signaling complex (DISC) and death effector domain (DED) filaments are critical for initiation of the extrinsic apoptotic pathway. Post-translational modifications (PTMs) of DED-containing DISC components such as FADD, procaspase-8, and c-FLIP comprise an additional level of apoptosis regulation, which is necessary to overcome the threshold for apoptosis induction. In this review we discuss the influence of PTMs of FADD, procaspase-8, and c-FLIP on DED filament assembly and cell death induction, with a focus on the 3D organization of the DED filament. In multicellular organisms, tissue homeostasis is maintained through a fine-tuned balance between cell proliferation and cell death [1.Eldeeb M.A. et al.Regulating apoptosis by degradation: the N-end rule-mediated regulation of apoptotic proteolytic fragments in mammalian cells.Int. J. Mol. Sci. 2018; 19E3414Crossref PubMed Scopus (24) Google Scholar, 2.Elmore S. Apoptosis: a review of programmed cell death.Toxicol. Pathol. 2007; 35: 495-516Crossref PubMed Scopus (8547) Google Scholar, 3.Wilson N.S. et al.Death receptor signal transducers: nodes of coordination in immune signaling networks.Nat. Immunol. 2009; 10: 348-355Crossref PubMed Scopus (425) Google Scholar, 4.Strasser A. et al.Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases.EMBO J. 2011; 30: 3667-3683Crossref PubMed Scopus (405) Google Scholar, 5.Taylor R.C. et al.Apoptosis: controlled demolition the Mol. PubMed Scopus Google and to programmed cell death et regulation of cell death, and of PubMed Scopus Google Apoptosis the extrinsic and the S. Apoptosis: a review of programmed cell death.Toxicol. Pathol. 2007; 35: 495-516Crossref PubMed Scopus (8547) Google The extrinsic is of death including and to death such as and et apoptosis by 2009; PubMed Scopus Google to the of proteins with death such as with death domain to the of in the formation of the death-inducing signaling complex (DISC) et proteins form a death-inducing signaling complex (DISC) with the J. PubMed Scopus Google et and death in Immunol. 2007; PubMed Scopus Google which in and of for DISC is of and of the DED of with of procaspase-8, and in the formation of which as a for and et death effector domain DISC a role for assembly in apoptotic cell PubMed Scopus Google Scholar, et of the death-inducing signaling and for a death effector domain PubMed Scopus Google Scholar, et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google DED to the N.S. et al.Death receptor signal transducers: nodes of coordination in immune signaling networks.Nat. Immunol. 2009; 10: 348-355Crossref PubMed Scopus (425) Google of cell death PubMed Scopus Google DED in a and and c-FLIP DED filaments are through and between et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google architecture of DED filaments an of control of cell are a role for modifications (PTMs) such as and in et regulation of cell death, and of PubMed Scopus Google et and PubMed Scopus Google Scholar, et with Sci. 2018; PubMed Scopus Google Scholar, a of and Immunol. PubMed Scopus Google Scholar, et of the other of apoptosis PubMed Scopus Google modifications in of in DED which is for and in a threshold for apoptosis et threshold in PubMed Scopus Google et cell the in 2018; PubMed Scopus Google In this we the role of PTMs in the of DISC and DED filament with a focus on the 3D organization of the DED components of the death-inducing signaling complex (DISC) a death effector domain form DED The of the DED filaments by of the et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google and in by and The DED filaments et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google The DED filaments a for the and of of DED the for formation of DED by the of and which the to to other The assembly of the DED filament is by of DED and the of and of and are by including the et death effector domain DISC a role for assembly in apoptotic cell PubMed Scopus Google is the of the of and c-FLIP et death effector domain DISC a role for assembly in apoptotic cell PubMed Scopus Google the formation of the DED in the of the DED filament DED filament is of the of to the for the and of procaspase-8, as the of the DED filament et death effector domain DISC a role for assembly in apoptotic cell PubMed Scopus Google Scholar, et of the death-inducing signaling and for a death effector domain PubMed Scopus Google Scholar, et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google and are the of and et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google and are by and a for the between in the filament In this the architecture of DED filament is on the of of DED and this between such as as well as between and The DED in a DED filament with a and a the DED filament a of the of et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google In the of the of et of by Sci. S. A. 2009; PubMed Scopus Google the of procaspase-8, the and to in The components of the death-inducing signaling complex (DISC) a death effector domain form DED The of the DED filaments by of the et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google and in by and The DED filaments et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google The DED filaments a for the and of The of DED the for formation of DED by the of and which the to to other The assembly of the DED filament is by of DED and the of and of and are by including the et death effector domain DISC a role for assembly in apoptotic cell PubMed Scopus Google is the of the of and c-FLIP et death effector domain DISC a role for assembly in apoptotic cell PubMed Scopus Google the formation of the DED in the of the DED filament DED filament is of the of to the for the and of procaspase-8, as the of the DED filament et death effector domain DISC a role for assembly in apoptotic cell PubMed Scopus Google Scholar, et of the death-inducing signaling and for a death effector domain PubMed Scopus Google Scholar, et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google and are the of and et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google and are by and a for the between in the filament In this the architecture of DED filament is on the of of DED and this between such as as well as between and The DED in a DED filament with a and a the DED filament a of the of et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google In the of the of et of by Sci. S. A. 2009; PubMed Scopus Google the of procaspase-8, the and to in is a signaling of The DED of filament and is for apoptosis et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google S. the between cancer and Immunol. 2018; PubMed Scopus Google The of is a for the initiation of DED filament by for apoptosis initiation S. the between cancer and Immunol. 2018; PubMed Scopus Google in DED in and by including and for signal et of tissue by with multiple Google in the DED the role in DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google and DED The of to the of in the formation of a is to DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google the of filament is is DED form the of is the of the DED et and of the PubMed Scopus Google et of and of with PubMed Scopus Google the DED and the of the of DED and in of the of the DED filament. In and with et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google for DED DED filament is et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google to the by the complex is of the DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google the the DED filament is in and of DED in the of of DED and as well as of the and of are in the of the DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google M.A. et and of c-FLIP and a c-FLIP control cell PubMed Scopus Google et of and of with PubMed Scopus Google J. et of and for DED DISC PubMed Scopus Google the role of the DED in In as in et and of c-FLIP as control of DED filament PubMed Scopus Google the and et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google by DED et and of the PubMed Scopus Google with an on the of of in for the of the in the DED filament in with (DED) in the DED of FADD, including death domain and of of of the DED filament with in DED are and is in is in DED is in The is et and of c-FLIP as control of DED filament PubMed Scopus Google 3D of the of filament with The of the is with a The for and as in is is on the of et and of c-FLIP as control of DED filament PubMed Scopus Google the role in DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google and DED The of to the of in the formation of a is to DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google the of filament is is DED form the of is the of the DED et and of the PubMed Scopus Google et of and of with PubMed Scopus Google the DED and the of the of DED and in of the of the DED filament. In and with et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google for DED DED filament is et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google to the by the complex is of the DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google the the DED filament is in and of DED in the of of DED and as well as of the and of are in the of the DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google M.A. et and of c-FLIP and a c-FLIP control cell PubMed Scopus Google et of and of with PubMed Scopus Google J. et of and for DED DISC PubMed Scopus Google the role of the DED in In as in et and of c-FLIP as control of DED filament PubMed Scopus Google the and et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google by DED et and of the PubMed Scopus Google with an on the of of in for the of the in the DED filament in of the on the DISC and to et proteins form a death-inducing signaling complex (DISC) with the J. PubMed Scopus Google et a is to the signaling PubMed Scopus Google and of S. the between cancer and Immunol. 2018; PubMed Scopus Google et as a of and in PubMed Scopus Google et role of the in the of death domain PubMed Scopus Google and et of by and in to apoptotic and cell 2011; PubMed Scopus Google of is by a of including and et of by and in to apoptotic and cell 2011; PubMed Scopus Google and to et of by PubMed Scopus Google the et role of the in the of death domain PubMed Scopus Google is by in to with the is a for et of by and in to apoptotic and cell 2011; PubMed Scopus Google of and in the cell a of and Immunol. PubMed Scopus Google et role of the in the of death domain PubMed Scopus Google et of by PubMed Scopus Google the et role of the in the of death domain PubMed Scopus Google In is the the of to with DISC assembly et proteins form a death-inducing signaling complex (DISC) with the J. PubMed Scopus Google et a is to the signaling PubMed Scopus Google In with this is of are of the and DED the of to of the complex by and et death domain complex by receptor 2009; PubMed Scopus Google and et death domain complex the of DISC assembly and Mol. PubMed Scopus Google the of is in the between the of on in with the of DED of the DED filament role of in the control of the DED filament assembly the of to role in the cell to cell death The other of is J. The a regulation of PubMed Scopus Google The of and the of J. et of by death signaling complex formation cell 2018; PubMed Scopus Google is an with and J. et of by death signaling complex formation cell 2018; PubMed Scopus Google The of of and to and of on the between of and the of to and DISC J. et of by death signaling complex formation cell 2018; PubMed Scopus Google In to the of the complex by and and et death domain complex by receptor 2009; PubMed Scopus Google et death domain complex the of DISC assembly and Mol. PubMed Scopus Google the and are in the of and a of the to of DED filament the DED is for with J. et of by death signaling complex formation cell 2018; PubMed Scopus Google of with of which in DED filament formation and the of and c-FLIP to the The of this to by of is which to of in the of et and of the death apoptosis and PubMed Scopus Google on and the of to in In the of is to of an checkpoint in the cell death this regulation to the DED of the The to to multiple and in the of the In is to by this to to the of and with et and to for PubMed Scopus Google to a for between and as this is the for by of this on the DED as The of this for in the cell to in PTMs such as and of to the and the of the the PTMs of influence the of with the of DED in DED filament formation regulation through PTMs of DISC by the of the DISC and the threshold for the of apoptosis et threshold in PubMed Scopus Google et cell the in 2018; PubMed Scopus Google a role for the DED in a DED is the of DED filament the of PTMs of DED for the regulation of DED filaments are for multiple as the in apoptosis et a is to the signaling PubMed Scopus Google of et is as and PubMed Scopus Google of procaspase-8, and are to the DISC et is as and PubMed Scopus Google and are the DED filaments the which a formation et death effector domain DISC a role for assembly in apoptotic cell PubMed Scopus Google with the and and The and the of this in the DED filament is of the of is which with the formation of M.A. et and of c-FLIP and a c-FLIP control cell PubMed Scopus Google PTMs of to an role in the of and level of apoptosis a PTMs and of with and of procaspase-8, to the et is with PubMed Scopus Google to the of DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google the is to the and in the of the DED filament this DED filament assembly of the of this and apoptotic et is with PubMed Scopus Google to the on is of the of the and are well to control by as apoptosis et of the other of apoptosis PubMed Scopus Google S. et on a of apoptosis J. PubMed Scopus Google et DISC by and the 35: PubMed Scopus Google is the between the and the to and the of the et DISC by and the 35: PubMed Scopus Google of is with in is to cell S. et on a of apoptosis J. PubMed Scopus Google Scholar, et DISC by and the 35: PubMed Scopus Google Scholar, S. et of a critical in cell PubMed Scopus Google Scholar, J. et with the of to cell and 2007; PubMed Scopus Google the domain et by of and in PubMed Scopus Google and et regulation of through of PubMed Scopus Google through in the of is by the is for and et regulation of through of PubMed Scopus Google et and PubMed Scopus Google In in is by the of which and apoptotic signaling et apoptosis by 30: PubMed Scopus Google of the of In this and in of cell death et of by and 2011; PubMed Scopus Google In to the of et of of by of PubMed Scopus Google occurs of the of the et of the other of apoptosis PubMed Scopus Google of a In and the which the et and of extrinsic apoptosis 2009; PubMed Scopus Google is of to and formation of to of et and of extrinsic apoptosis 2009; PubMed Scopus Google of are et to and cell PubMed Scopus Google of the domain of as well as of in et to and cell PubMed Scopus Google and the of in the of other to the to the of of the DISC et of the other of apoptosis PubMed Scopus Google et cancer cell by of PubMed Scopus Google to the to the and to critical for In with is in cancer cell and and et cancer cell by of PubMed Scopus Google is by which to with the to the and the domain et a threshold for extrinsic apoptosis by with a PubMed Scopus Google to of which the apoptotic threshold et a threshold for extrinsic apoptosis by with a PubMed Scopus Google to which and the of to apoptosis et apoptosis by the of apoptotic signaling through of PubMed Scopus Google In of the is the on are to this and of to and as well as the between PTMs with the assembly of the DED filaments the formation of the DED filaments in the threshold for apoptosis and in the the DED filaments is controlled by c-FLIP proteins M.A. et and of c-FLIP and a c-FLIP control cell PubMed Scopus Google et architecture of the DED the regulation of by DED proteins c-FLIP and PubMed Scopus Google and c-FLIP and and are to the DISC S. et proteins of and death PubMed Scopus Google In c-FLIP and S. et proteins of and death PubMed Scopus Google c-FLIP proteins DED in the and and and in are to the DED filament in a as well as in an on on level et of signaling a and role of PubMed Scopus Google The of is formation of in which the of is by which et of by Sci. S. A. 2009; PubMed Scopus Google c-FLIP and by with in the DED filaments M.A. et and of c-FLIP and a c-FLIP control cell PubMed Scopus Google et architecture of the DED the regulation of by DED proteins c-FLIP and PubMed Scopus Google et and of c-FLIP as control of DED filament PubMed Scopus Google of c-FLIP in the DED and c-FLIP and and of and comprise and and and as well as a a and an role of c-FLIP the DISC and DED filaments a of c-FLIP to in a M.A. et and of c-FLIP and a c-FLIP control cell PubMed Scopus Google the of c-FLIP to with in the DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google et architecture of the DED the regulation of by DED proteins c-FLIP and PubMed Scopus Google and the of c-FLIP to J. et of and for DED DISC PubMed Scopus Google the and the formation of of c-FLIP with of of c-FLIP the DED to the formation of The formation is to the of to the The of of c-FLIP to c-FLIP with the of the other for to J. et of and for DED DISC PubMed Scopus Google The of c-FLIP to with in the of et and of c-FLIP as control of DED filament PubMed Scopus Google 3D of c-FLIP to the of c-FLIP a of the of c-FLIP in are on the of such as are to c-FLIP et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google M.A. et and of c-FLIP and a c-FLIP control cell PubMed Scopus Google et the role of in the of PubMed Scopus Google the role of c-FLIP in the DISC by et an PubMed Scopus Google a the of DED to the of of c-FLIP et and of c-FLIP as control of DED filament PubMed Scopus Google DED the filament in the by to the of the filament in the by to the of the c-FLIP domain c-FLIP to the of the DED filament et and of c-FLIP as control of DED filament PubMed Scopus Google of the DED filament is of of procaspase-8, and in DED filaments the in the of DED filaments to the formation of DED filaments by multiple DISC to in the (DED) of c-FLIP of the DED filament with c-FLIP to the et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google DED are and is in is in with death domain DED is in of c-FLIP is in of c-FLIP is in a of filament with c-FLIP to the by et and of c-FLIP as control of DED filament PubMed Scopus Google The in the of the DED filament are on c-FLIP J. et of and for DED DISC PubMed Scopus Google The for procaspase-8, and as in is The of the is with a c-FLIP c-FLIP c-FLIP and c-FLIP and and of and comprise and and and as well as a a and an role of c-FLIP the DISC and DED filaments a of c-FLIP to in a M.A. et and of c-FLIP and a c-FLIP control cell PubMed Scopus Google the of c-FLIP to with in the DED filament et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google et architecture of the DED the regulation of by DED proteins c-FLIP and PubMed Scopus Google and the of c-FLIP to J. et of and for DED DISC PubMed Scopus Google the and the formation of of c-FLIP with of of c-FLIP the DED to the formation of The formation is to the of to the The of of c-FLIP to c-FLIP with the of the other for to J. et of and for DED DISC PubMed Scopus Google The of c-FLIP to with in the of et and of c-FLIP as control of DED filament PubMed Scopus Google 3D of c-FLIP to the of c-FLIP a of the of c-FLIP in are on the of such as are to c-FLIP et of DED filament assembly and regulation of the death-inducing signaling PubMed Scopus Google M.A. et and of c-FLIP and a c-FLIP control cell PubMed Scopus Google et the role of in the of PubMed Scopus Google the role of c-FLIP in the DISC by et an PubMed Scopus Google a the of DED to the of of c-FLIP et and of c-FLIP as control of DED filament PubMed Scopus Google DED the filament in the by to the of the filament in the by to the of the c-FLIP domain c-FLIP to the of the DED filament et and of c-FLIP as control of DED filament PubMed Scopus Google of the DED filament is of of procaspase-8, and in DED filaments the in the of DED filaments to the formation of DED filaments by multiple DISC to in of c-FLIP to in the of apoptosis S. et proteins of and death PubMed Scopus Google c-FLIP and of and the between and of In the to a for and of c-FLIP et and of c-FLIP PubMed Scopus Google et to cell death by PubMed Scopus Google is to as the signal for of c-FLIP in the of DED the by of and and et of is by PubMed Scopus Google in the of the of the of c-FLIP is by et of is by PubMed Scopus Google A. et c-FLIP and 2009; PubMed Scopus Google is of c-FLIP with DISC and DED filaments are by and is the influence the of c-FLIP to DISC A. et c-FLIP and 2009; PubMed Scopus Google and are in the to which to the A. et PubMed Scopus Google the DED-containing of which is a of the of S. et proteins of and death PubMed Scopus Google A. et PubMed Scopus Google is a for to the between and this of c-FLIP in In which of in the of this et of is the signaling in 2009; PubMed Scopus Google Scholar, et regulation of c-FLIP and in of signaling in PubMed Scopus Google Scholar, et and and in Immunol. 2009; 10: PubMed Scopus Google to of and which in on and to and of by et of is the signaling in 2009; PubMed Scopus Google Scholar, et regulation of c-FLIP and in of signaling in PubMed Scopus Google Scholar, et and and in Immunol. 2009; 10: PubMed Scopus Google c-FLIP is by a which as an to control the and of the and et and of c-FLIP PubMed Scopus Google et of is the signaling in 2009; PubMed Scopus Google et and and in Immunol. 2009; 10: PubMed Scopus Google Scholar, S. et death receptor and to of apoptosis by in cancer 2007; PubMed Scopus Google Scholar, et therapy of cancer a and a receptor Sci. S. A. PubMed Scopus Google c-FLIP to et apoptosis through of of PubMed Scopus Google to the for c-FLIP to c-FLIP et apoptosis through of of PubMed Scopus Google the of including the of c-FLIP are c-FLIP The of assembly complex with the of which to of c-FLIP et of by to 2018; PubMed Scopus Google on c-FLIP are to in the of and et of by to 2018; PubMed Scopus Google with of of et of by to 2018; PubMed Scopus Google and et apoptosis through of of PubMed Scopus Google of and to an in and of apoptotic the of are the domain and with the of to the DED filament an of to an of which to an of of the of c-FLIP to the of in of as a of which is et apoptosis through of of PubMed Scopus Google c-FLIP to an for apoptosis regulation of the of control of c-FLIP the regulation of the level on PTMs c-FLIP which is controlled by the between and regulation of c-FLIP as well as of The the of c-FLIP in the which the to cell death to regulation to c-FLIP with the DED as PTMs to the of c-FLIP proteins in the on the PTMs of the DED the level of c-FLIP in the the of the DISC formation is well we are to the role of PTMs of DISC components in the of the extrinsic apoptotic signaling pathway. we the role of FADD, and c-FLIP modifications in the of are PTMs the assembly of the of the of to the level of the and the PTMs of proteins DED for the assembly of the DED filaments to this of PTMs is to the of the DED-containing proteins FADD, and and control PTMs signaling the PTMs of DISC components an checkpoint to the signaling and a threshold for apoptosis induction. which in is additional PTMs of the DISC which the extrinsic apoptotic PTMs to the assembly of the PTMs regulation of the of DED-containing PTMs signaling the PTMs of DISC components the signaling and threshold for apoptosis PTMs to the assembly of the PTMs regulation of the of DED-containing PTMs signaling the PTMs of DISC components the signaling and threshold for apoptosis and of by the and for and for

Topics & Concepts