Table 1 Regulators of the cytotoxic potential of RIPK1.

From: The resurrection of RIP kinase 1 as an early cell death checkpoint regulator—a potential target for therapy in the necroptosis era

Category

Regulator

Function

proposed mechanism

Outcome

Reference

E3 Ub ligases

TRAF2/5

K63-linked polyubiquitination of RIPK1 in complex-I

Preventing RIPK1 dissociation from complex-I

Inhibits complex-IIb-mediated RDA and necroptosis

36,41,43

cIAP1/2

K63/K11-linked polyubiquitination of RIPK1 in complex-I

Preventing RIPK1 dissociation from complex-I

Inhibits complex-IIb-mediated RDA and necroptosis

44,45,46,

LUBAC (HOIL, HOIP, SHARPIN)

M1-linked, linear ubiquitination of RIPK1 in complex-I

Enhanced tethering of RIPK1 in complex-I

Inhibits complex-IIb-mediated RDA and necroptosis by stabilization of complex-I

35,50,51

A20

K48-linked polyubiquitination of RIPK1 in complex-I

Proteasomal degradation of RIPK1

Inhibits RDA

74,75

MIB2

K63(?)-linked polyubiquitination of RIPK1 in complex-I

Inhibition of RIPK1 activity

Inhibits RDA

64

PELI1

K63-linked ubiquitination of RIPK1 in complex-IIb or necrosome

promotes the interaction of RIPK1 and RIPK3

Promotes necroptosis

140,143

DUBs

A20

Deubiquitination of K63-Ub chains of RIPK1

Decreases RIPK1 activity by stabilizing M1-linked Ub chains

Inhibits complex-II formation and RDA and necroptosis

74,81,82

CYLD

Deubiquitination of K63/M1-Ub chains of RIPK1

Decreases the overall ubiquitination status of complex-I

Promotes complex-IIb-mediated RDA and necroptosis

89,90,91

Cezanne

Deubiquitination of K63(?)-Ub chains of RIPK1

Suppresses the build-up of polyubiquitinated RIPK1 in complex-I

promotes complex-II-mediated apoptosis

98,99

Adapters

ANKRD13a

UIM protein interacts with ubiquitinated RIPK1

inhibition of RIPK1 transition into complex-II

Inhibits complex-II-mediated apoptosis and necroptosis

18

ABIN-1

Ub-binding protein in complex-I

Regulation of the recruitment of A20 into complex-I

Inhibits RDA and necroptosis

62,63

epsin 1/2

Ub-binding endocytic adapters in complex-I

Regulation of IKKs recruitment in complex-I assembly by interacting with LUBAC

Inhibits complex-II-mediated apoptosis

72

  1. Abbreviations: RDA RIPK1-dependent apoptosis, RIPK1 receptor-interacting serine threonine protein kinase 1, TRAF2/5 TNF receptor-associated factor 2/5, cIAP1/2 cellular inhibitor of apoptosis 1/2, LUBAC linear ubiquitin chain assembly complex, HOIL heme-oxidized IRP2 ubiquitin ligase, HOIP HOIL-1-interacting protein, SHARPIN SHANK-associated RH domain-interacting protein, MIB2 Mind Bomb-2, PELI1 Pellino 1, CYLD cylindromatosis lysine 63 deubiquitinase, Cezanne cellular zinc finger anti-NF-kappa-B protein, ANKRD13a ankyrin repeat domain 13 A, ABIN-1 A20-binding inhibitor of NF-kappaB activation 1.
Back to article page