Dependence of Site-2 Protease Cleavage of ATF6 on Prior Site-1 Protease Digestion Is Determined by the Size of the Luminal Domain of ATF6
Department of Biological Sciences, Columbia University, New York, New York 10027, USA. Journal of Biological Chemistry
(Impact Factor: 4.57).
11/2004; 279(41):43046-51. DOI: 10.1074/jbc.M408466200
ATF6 is an endoplasmic reticulum (ER) membrane-anchored transcription factor activated by regulated intramembrane proteolysis in the ER stress response. The release of the cytosolic transcription factor domain of ATF6 requires the sequential processing by the Golgi site-1 and site-2 proteases (S1P and S2P). It has been unclear why S2P proteolysis relies on previous site-1 cleavage. One possibility is that S2P localizes to a different cellular compartment than S1P; however, here we show that S2P localizes to the same compartment as S1P, the cis/medial-Golgi. In addition, we have re-localized S1P and S2P to the ER with brefeldin A and find that the sequential cleavage of ATF6 is reconstituted in the ER. The mapping of the region of ATF6 required for sequential S1P and S2P cleavage showed that short luminal domains resulted in S1P-independent S2P cleavage. The addition of artificial domains onto these short ATF6 luminal domains restored the S1P dependence of S2P cleavage, suggesting that it is the size rather than specific sequences in the luminal domain that determines the S1P dependence of S2P cleavage. These results suggest that the bulky ATF6 luminal domain blocks S2P cleavage and that the role of S1P is to reduce the size of the luminal domain to prepare ATF6 to be an optimal S2P substrate.
Available from: Renu Srivastava
- "It is interesting to note that bZIP28Δ355 lacks a S1P processing site. Cleavage at the S1P site is usually considered to be a prerequisite for S2P cleavage, which releases the transcriptional component of stress sensor/transducer from the Golgi for relocation to the nucleus (Espenshade et al., 1999; Shen and Prywes, 2004). This implies that S1P cleavage is not required for S2P proteolysis as long as the C-terminal tail of bZIP28 has been removed. "
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ABSTRACT: Two classes of ER stress sensors are known in plants, membrane-associated basic leucine zipper (bZIP) transcription factors and RNA splicing factors. ER stress occurs under adverse environmental conditions and results from the accumulation of misfolded or unfolded proteins in the ER lumen. One of the membrane-associated transcription factors activated by heat and ER stress agents is bZIP28. In its inactive form, bZIP28 is a type II membrane protein with a single pass transmembrane domain, residing in the ER. bZIP28's N-terminus, containing a transcriptional activation domain, is oriented towards the cytoplasm and its C-terminal tail is inserted into the ER lumen. In response to stress, bZIP28 exits the ER and moves to the Golgi where it is proteolytically processed, liberating its cytosolic component which relocates to the nucleus to upregulate stress-response genes. bZIP28 is thought to sense stress through its interaction with the major ER chaperone, binding immunoglobulin protein (BIP). Under unstressed conditions, BIP binds to intrinsically disordered regions in bZIP28's lumen-facing tail and retains it in the ER. A truncated form of bZIP28, without its C-terminal tail is not retained in the ER but migrates constitutively to the nucleus. Upon stress, BIP releases bZIP28 allowing it to exit the ER. One model to account for the release of bZIP28 by BIP is that BIP is competed away from bZIP28 by the accumulation of misfolded proteins in the ER. However, other forces such as changes in energy charge levels, redox conditions or interaction with DNAJ proteins may also promote release of bZIP28 from BIP. Movement of bZIP28 from the ER to the Golgi is assisted by the interaction of elements of the COPII machinery with the cytoplasmic domain of bZIP28. Thus, the mobilization of bZIP28 in response to stress involves the dissociation of factors that retain it in the ER and the association of factors that mediate its further organelle-to-organelle movement.
Available from: Mark A Lawson
- "ATF6 exists as an ER membrane-resident transcription factor that is anchored by a luminal domain. Accumulation of unfolded proteins triggers transport of vesicles containing ATF6 to the golgi where the luminal domain is sequentially removed by S1P and S2P proteases normally associated with sterol response element binding protein processing (Ye et al., 2000; Shen and Prywes, 2004). The exact mechanisms of proteolytic processing of ATF6 and the nature of luminal-domain sensing of ER stress are not well defined but it is proposed that the unusual structure of the luminal domain contain redox-sensitive disulfide bridges or chaperone interaction domains that monitor the status of the ER (Walter and Ron, 2011). "
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ABSTRACT: The study of gene expression in gonadotropes has largely focused on the variety of mechanisms regulating transcription of the gonadotropin genes and ancillary factors that contribute to the overall phenotype and function of these cells in reproduction. However, there are aspects of the response to GNRH signaling that are not readily explained by changes at the level of transcription. As our understanding of regulation at the level of mRNA translation has increased, it has become evident that GNRH receptor signaling engages multiple aspects of translational regulation. This includes activation of cap-dependent translation initiation, translational pausing caused by the unfolded protein response and RNA binding protein interaction. Gonadotropin mRNAs and the mRNAs of other factors that control the transcriptional and signaling responses to GNRH have been identified as targets of regulation at the level of translation. In this review we examine the impact of translational control of the expression of gonadotropin genes and other genes relevant to GNRH-mediated control of gonadotrope function.
Available from: Patricia Renard
- "When the ER is overwhelmed by the accumulation of unfolded proteins, BiP preferentially associates with them and dissociates from the three receptor/sensor proteins (Bertolotti et al., 2000). Both IRE1 and PERK, free to homodimerise, get activated by auto-transphosphorylation, whereas ATF6 moves to the Golgi, where it is released after cleavage in the cytosol and translocates into the nucleus (Shen and Prywes, 2004). Although the three UPR branches of the UPR signalling pathway are simultaneously activated upon ER stress, the behaviour of each of these branches varies markedly in time after the onset of the stress (Lin et al., 2007). "
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ABSTRACT: Over the past years, knowledge and evidence about the existence of crosstalks between cellular organelles and their potential effects on survival or cell death have been constantly growing. More recently, evidence accumulated showing an intimate relationship between endoplasmic reticulum and mitochondria. These close contacts not only establish extensive physical links allowing exchange of lipids and calcium but they can also coordinate pathways involved in cell life and death. It is now obvious that ER dysfunction/stress and Unfolded Protein Response (UPR) as well as mitochondria play major roles in apoptosis. However, while the effects of major ER stress on cell death have been largely studied and reviewed, it becomes more and more evident that cells might regularly deal with sublethal ER stress, a condition that does not necessarily lead to cell death but might affect the function/activity of other organelles such as mitochondria. In this review, we will particularly focus on these new, interesting and intriguing metabolic and morphological events that occur during the early adaptative phase of the ER stress, before the onset of cell death, and that remain largely unknown. Relevance and implication of these mitochondrial changes in response to ER stress conditions for human diseases such as type II diabetes and Alzheimer's disease will also be considered. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
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