ADP ribosylation adapts an ER chaperone response to short-term fluctuations in unfolded protein load

Chambers, Joseph E.; Petrova, Kseniya; Tomba, Giulia; Vendruscolo, Michele; Ron, David

doi:10.1083/jcb.201202005

Cited by 94 publications

(106 citation statements)

References 58 publications

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“…In the absence of stress, BiP has been shown to be a major ADP-ribosylated protein in mammalian cells 7 and is thought to be phosphorylated 8; 9 . However, whenever the load of unfolded proteins increases in the ER, the amount of modified BiP decreases 7; 9–11 . Accordingly, it has been suggested that the ADP-ribosylated or phosphorylated forms of BiP represent a pool of inactive oligomeric molecules that can quickly be reactivated when needed 7; 12; 13 (Fig.…”

Section: The Atpase Cycle Of Bip In the Er Environmentmentioning

confidence: 99%

“…Despite this and other 14–16 circumstantial evidence suggesting that BiP’s activity in vivo might be affected by post-translational modifications, it remains unclear how these modifications are controlled in response to physiological cues. Although neither the kinase nor ADP-ribosyltransferase has been identified, recently the ADP-ribosylation site of BiP was mapped to two Arg residues within its s ubstrate b inding d omain (SBD) 11 . Modification of these residues would interfere with substrate binding and thus explain earlier observations that only unmodified BiP is bound to substrates.…”

Section: The Atpase Cycle Of Bip In the Er Environmentmentioning

confidence: 99%

“…Substrates and ATP can induce dissociation of BiP oligomers 15; 17 , thereby reshuffling BiP into its functional ATPase cycle in the ER. As mutation of these two Arg residues abolished all post-translational modifications of BiP, the role of phosphorylation has been questioned 11 . Very recently two groups reported that the NBD of drosophila 18 and human 19 BiP can be modified by AMPylation.…”

Section: The Atpase Cycle Of Bip In the Er Environmentmentioning

confidence: 99%

See 2 more Smart Citations

BiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions

Behnke

Feige

Hendershot

2015

Journal of Molecular Biology

164

168

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BiP is the endoplasmic reticulum (ER) orthologue of the Hsp70 family of molecular chaperones and is intricately involved in most functions of this organelle through its interactions with a variety of substrates and regulatory proteins. Like all Hsp70 family members, the ability of BiP to bind and release unfolded proteins is tightly regulated by a cycle of ATP binding, hydrolysis, and nucleotide exchange. As a characteristic of the Hsp70 family, multiple DnaJ-like co-factors exist that can target substrates to BiP and stimulate its ATPase activity to stabilize the binding of BiP to substrates. However, only in the past decade have nucleotide exchange factors (NEFs) for BiP been identified, which has shed light not only on the mechanism of BiP assisted folding in the ER but also on Hsp70 family members that reside throughout the cell. We will review the current understanding of the ATPase cycle of BiP in the unique environment of the ER and how it is regulated by the NEFs, Grp170 and Sil1, both of which perform unanticipated roles in various biological functions and disease states.

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Section: The Atpase Cycle Of Bip In the Er Environmentmentioning

confidence: 99%

Section: The Atpase Cycle Of Bip In the Er Environmentmentioning

confidence: 99%

Section: The Atpase Cycle Of Bip In the Er Environmentmentioning

confidence: 99%

See 1 more Smart Citation

BiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions

Behnke

Feige

Hendershot

2015

Journal of Molecular Biology

164

168

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“…Several post-translational modifications have been suggested to regulate BiP activities, including AMPylation [14–16] and oligomerization [17]. In addition, it has been proposed that BiP is ADP-ribosylated [18, 19] and phosphorylated [19], although it has been put forward that these two postulated modifications may reflect misattributed AMPylation events [15]. …”

Section: Introductionmentioning

confidence: 99%

A Conserved Cysteine within the ATPase Domain of the Endoplasmic Reticulum Chaperone BiP is Necessary for a Complete Complement of BiP Activities

Marsh

Sevier

2016

Journal of Molecular Biology

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Among the amino acids, cysteine stands apart based on its highly reactive sulfur group. In general, cysteine is underrepresented in proteins. Yet when present, the features of cysteine often afford unique function. We have shown previously that a cysteine within the ATPase domain of yeast BiP (Kar2) serves as a sensor of the endoplasmic reticulum (ER) redox environment [1, 2]. Under conditions of increased oxidant (oxidative stress) this cysteine becomes oxidized, changing Kar2 from an ATP-dependent foldase to an ATP-independent holdase. We were struck by the high degree of conservation for this cysteine between BiP orthologs, and we sought to determine how cysteine substitution impacts Kar2 function. We observed no single amino acid replacement is capable of recreating the range of functions that can be achieved by wild-type Kar2 with its cysteine in either the unmodified or oxidized states. However, we were able to generate mutants that could selectively replicate the distinct activities exhibited by either unmodified or oxidized Kar2. We found that the ATPase activity displayed by unmodified Kar2 is fully maintained when Cys63 is replaced with Ala or Val. Conversely, we demonstrate that several amino acid substitutions (including His, Phe, Pro, Trp, Tyr) support an enhanced viability during oxidative stress associated with oxidized Kar2, although these alleles are compromised as an ATPase. We reveal the range of activity demonstrated by wild-type Kar2 can be replicated by co-expression of Kar2 mutants that mimic either the unmodified or oxidized Kar2 state, allowing for growth during standard and oxidative stress conditions.

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“…Known targets of MAR modification include the cytoskeletal proteins actin 36, 37 and desmin 38 , the protein folding chaperone GRP78 (also known as BiP) 39–42 and heterotrimeric G-proteins 43–47 . Each of these proteins is MARylated on arginines instead of the canonical lysine, glutamate or aspartate residues known to be PARylated by PARPs 48–50 .…”

Section: Mar Versus Parmentioning

confidence: 99%

New PARP targets for cancer therapy

2014

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Poly(ADP-ribose) polymerases (PARPs) modify target proteins post-translationally with poly(ADP-ribose) (PAR) or mono(ADP-ribose) (MAR) using NAD+ as substrate. The best-studied PARPs generate PAR modifications and include PARP1 and the tankyrase PARP5a, both of which are targets for cancer therapy with inhibitors in either clinical trials or preclinical development. There are 15 additional PARPs, the majority of which modify proteins with MAR, and their biology is less well understood. Recent data identify potentially cancer relevant functions for these PARPs, indicating that we need to understand more about these PARPs in order to target them effectively.

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ADP ribosylation adapts an ER chaperone response to short-term fluctuations in unfolded protein load

Abstract: Inactivating ADP ribosylation of the ER chaperone BiP is a rapidly reversible mechanism for buffering acute changes in unfolded protein load.

Cited by 94 publications

References 58 publications

BiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions

BiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions

A Conserved Cysteine within the ATPase Domain of the Endoplasmic Reticulum Chaperone BiP is Necessary for a Complete Complement of BiP Activities

New PARP targets for cancer therapy

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