TY - JOUR
T1 - Transcription factors activated through RIP (regulated intramembrane proteolysis) and RAT (regulated alternative translocation)
AU - Ye, Jin
N1 - Funding Information:
Funding and additional information—This work was supported by National Institutes of Health Grants GM-116106 and HL-20948 and Welch Foundation Grant I-1832 (to J. Y.). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2020 Ye.
PY - 2020/7/24
Y1 - 2020/7/24
N2 - Transmembrane proteins are membrane-anchored proteins whose topologies are important for their functions. These properties enable regulation of certain transmembrane proteins by regulated intramembrane proteolysis (RIP) and regulated alternative translocation (RAT). RIP enables a protein fragment of a transmembrane precursor to function at a new location, and RAT leads to an inverted topology of a transmembrane protein by altering the direction of its translocation across membranes during translation. RIP mediated by site-1 protease (S1P) and site-2 protease (S2P) is involved in proteolytic activation of membrane-bound transcription factors. In resting cells, these transcription factors remain in the endoplasmic reticulum (ER) as inactive transmembrane precursors. Upon stimulation by signals within the ER, they are translocated from the ER to the Golgi. There, they are cleaved first by S1P and then by S2P, liberating their N-terminal domains from membranes and enabling them to activate genes in the nucleus. This signaling pathway regulates lipidmetabolism, unfolded protein responses, secretion of extracellular matrix proteins, and cell proliferation. Remarkably, ceramide-induced RIP of cAMP response element- binding protein 3-like 1 (CREB3L1) also involves RAT. In resting cells, RIP of CREB3L1 is blocked by transmembrane 4 L6 family member 20 (TM4SF20). Ceramide inverts the orientation of newly synthesized TM4SF20 in membranes through RAT, converting TM4SF20 from an inhibitor to an activator of RIP of CREB3L1. Here, I review recent insights into RIP of membranebound transcription factors, focusing on CREB3L1 activation through both RIP and RAT, and discuss current open questions about these two signaling pathways.
AB - Transmembrane proteins are membrane-anchored proteins whose topologies are important for their functions. These properties enable regulation of certain transmembrane proteins by regulated intramembrane proteolysis (RIP) and regulated alternative translocation (RAT). RIP enables a protein fragment of a transmembrane precursor to function at a new location, and RAT leads to an inverted topology of a transmembrane protein by altering the direction of its translocation across membranes during translation. RIP mediated by site-1 protease (S1P) and site-2 protease (S2P) is involved in proteolytic activation of membrane-bound transcription factors. In resting cells, these transcription factors remain in the endoplasmic reticulum (ER) as inactive transmembrane precursors. Upon stimulation by signals within the ER, they are translocated from the ER to the Golgi. There, they are cleaved first by S1P and then by S2P, liberating their N-terminal domains from membranes and enabling them to activate genes in the nucleus. This signaling pathway regulates lipidmetabolism, unfolded protein responses, secretion of extracellular matrix proteins, and cell proliferation. Remarkably, ceramide-induced RIP of cAMP response element- binding protein 3-like 1 (CREB3L1) also involves RAT. In resting cells, RIP of CREB3L1 is blocked by transmembrane 4 L6 family member 20 (TM4SF20). Ceramide inverts the orientation of newly synthesized TM4SF20 in membranes through RAT, converting TM4SF20 from an inhibitor to an activator of RIP of CREB3L1. Here, I review recent insights into RIP of membranebound transcription factors, focusing on CREB3L1 activation through both RIP and RAT, and discuss current open questions about these two signaling pathways.
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U2 - 10.1074/jbc.REV120.012669
DO - 10.1074/jbc.REV120.012669
M3 - Review article
C2 - 32487748
AN - SCOPUS:85088676948
SN - 0021-9258
VL - 295
SP - 10271
EP - 10280
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 30
ER -