HSP-16.1 is a heat-inducible small heat shock protein (sHSP) of the alpha-crystallin/HSP20 family, encoded by two identical genes, hsp-16.1 (T27E4.8) and hsp-16.11 (T27E4.2), which form the arms of an inverted repeat on chromosome V where each is paired head-to-head with hsp-16.48 or hsp-16.49. HSP-16.1 belongs to the same sHSP subclass as HSP-16.2. Like the other HSP-16 proteins it is not expressed under normal conditions and is strongly induced by heat (and by hypoxia and oxidative stress) through HSF-1 and heat shock elements in the shared intergenic promoter. It acts as an ATP-independent holdase chaperone that binds unfolding proteins to prevent aggregation and keep them competent for refolding; HSP-16 proteins co-immunoprecipitate and co-localize with intracellular amyloid-beta in transgenic worms. A pool of HSP-16.1 localizes to the Golgi, where it works with the Ca2+/Mn2+ pump PMR-1 to maintain Ca2+ homeostasis and mediates the protection of neurons against heat-stroke-induced necrosis conferred by thermal preconditioning. HSF-1-dependent sHSPs are also required for resistance to Gram-negative pathogens.
Definition: Binding to an unfolded or misfolded protein to prevent its aggregation without actively catalyzing refolding. The holdase maintains the client protein in a soluble, folding-competent state. This is mechanistically distinct from foldase activity (GO:0044183) and from carrier-holdase activity (GO:0140309).
Justification: hsp-16.1: an alpha-crystallin-domain small HSP of the C. elegans HSP-16 family; the paralogue HSP-16.2 suppresses thermal aggregation of citrate synthase ATP-independently. Obsolete GO:0051082 captured binding only; GO:0044183 requires assisting folding, and GO:0140309 (relabelled 'unfolded protein holdase activity') keeps a carrier-specific definition requiring escort to an acceptor molecule or location, which is not demonstrated here. See go-ontology#30552.
Parent term: molecular_function
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA for nuclear activity propagated from the sHSP family node PTN000897708 (zebrafish and other vertebrate members as descendant evidence). Reason: Vertebrate sHSPs enter the nucleus under stress and the target is within the clade; there is no direct C. elegans evidence for nuclear HSP-16.1. Retained as a plausible but non-core location (the hsp-16.2 review accepted the same IBA). |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for cytoplasm from node PTN000897708, with several C. elegans sHSPs as descendant evidence. Reason: HSP-16 proteins are soluble cytoplasmic chaperones without targeting signals; immunohistochemistry detects stress-induced HSP16s in many tissues. Supporting Evidence: PMID:11001875 Immunohistochemical data on 10 of the 14 small heat-shock (smHSPs) proteins in fourth larval stage and adult Caenorhabditis elegans show that the tissues expressing the greatest number of smHSPs are vulva (HSP12s, HSP43 and, under stress, HSP16s) |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of cytoplasm. Reason: Redundant with the IBA but correct for a soluble sHSP. |
| GO:0005797 Golgi medial cisterna | IDA PMID:22972192 Small heat-shock proteins protect from heat-stroke-associate... | ACCEPT | Summary: Kourtis et al. showed that HSP-16.1 localizes to the Golgi, where it acts with the Ca2+/Mn2+ pump PMR-1 to maintain Ca2+ homeostasis and protect neurons against heat-stroke-induced necrosis. Reason: Direct localization evidence; the Golgi pool of HSP-16.1 is the one linked to its best-characterized in vivo protective function. The specific medial-cisterna term was chosen by the curator from the full text, which we could not read; accepted as given. Supporting Evidence: PMID:22972192 HSP-16.1 localizes to the Golgi, where it functions with the Ca(2+)- and Mn(2+)-transporting ATPase PMR-1 to maintain Ca(2+) homeostasis under heat stroke. PMID:22972192 The heat-shock transcription factor HSF-1 and the small heat-shock protein HSP-16.1 mediate cytoprotection by preconditioning. |
| GO:0009408 response to heat | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for response to heat from node PTN000897708. Reason: The hsp-16 genes are the archetypal heat-inducible genes of C. elegans: never constitutively expressed and strongly induced by heat via HSF-1 and heat shock elements in the shared intergenic promoters. Supporting Evidence: PMID:1550963 Transcription of the hsp16-lacZ transgenes was totally heat-shock dependent and resulted in the rapid synthesis of detectable levels of beta-galactosidase. |
| GO:0009408 response to heat | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of response to heat. Reason: Redundant with the IBA and IEP annotations but correct. |
| GO:0009408 response to heat | IEP PMID:1550963 Temporal and spatial expression patterns of the small heat s... | ACCEPT | Summary: hsp16-lacZ reporter study showing strictly heat-shock-dependent expression of the hsp16 gene pairs, with tissue differences between pairs and no inducibility in germline or early embryo. Reason: Foundational expression evidence for the heat inducibility that defines the hsp-16 genes. Supporting Evidence: PMID:1550963 Transcription of the hsp16-lacZ transgenes was totally heat-shock dependent and resulted in the rapid synthesis of detectable levels of beta-galactosidase. PMID:1550963 they are not heat inducible during gametogenesis or early embryogenesis |
| GO:0030968 endoplasmic reticulum unfolded protein response | IEP PMID:12186849 A survival pathway for Caenorhabditis elegans with a blocked... | KEEP AS NON CORE | Summary: Microarray study: hsp-16 genes are among the genes induced by tunicamycin in an xbp-1-dependent manner (Table I). Reason: The induction is real but HSP-16.1 is a cytoplasmic sHSP; its induction during ER stress is a secondary output, not participation in an ER-lumenal folding response. Non-core. Supporting Evidence: PMID:12186849 Of these 34 genes, 26 were uninduced or induced to significantly lower levels (P < 0.05) in the xbp-1 mutant strain. |
| GO:0036498 IRE1-mediated unfolded protein response | HEP PMID:12186849 A survival pathway for Caenorhabditis elegans with a blocked... | KEEP AS NON CORE | Summary: Same microarray result: tunicamycin induction of hsp-16 transcripts is attenuated in xbp-1 mutants. Reason: xbp-1 dependence places the expression change downstream of IRE-1/XBP-1, but the sHSP is an output of that response, not a component of the signalling pathway. Non-core. Supporting Evidence: PMID:12186849 Of these 34 genes, 26 were uninduced or induced to significantly lower levels (P < 0.05) in the xbp-1 mutant strain. |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PAINT IBA for protein refolding from node PTN000897708. HSP-16.1 is an ATP-independent holdase that sequesters unfolding polypeptides to prevent aggregation rather than catalyzing protein refolding itself. Reason: sHSPs of the alpha-crystallin/HSP20 family (PANTHER:PTN000897708) do not catalyze protein refolding themselves; they bind unfolding intermediates ATP-independently to prevent irreversible aggregation and maintain them in a state from which the ATP-dependent HSP70 chaperone system subsequently refolds them. Although GO:0042026 (protein refolding) is a biological process term, sHSP holdase sequestration occurs during stress to prevent irreversible aggregation independently of whether the client's downstream fate is HSP70-mediated refolding or proteasomal/autophagic degradation, and sHSPs are neither subunits nor cofactors of the ATP-dependent HSP70/J-domain/NEF refolding reaction once substrate is released, so attributing the downstream protein refolding process (GO:0042026) to the upstream stress holdase conflates distinct proteostasis steps (go-ontology#30552). Marked as over-annotated, consistent with the sibling C. elegans hsp-16 and vertebrate sHSP/alpha-crystallin reviews. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION GRANULARITY MISMATCH Sources checked: PANTHER:PTN000897708 · PTN000897708 SUPPORTS SOURCE BUT NOT TARGET Ancestral sHSP node placement (Eumetazoa, taxon:6072) is sound for chaperone-like holdase function, but GO:0042026 (protein refolding) ascribes to the sHSP an active foldase step performed by ATP-dependent chaperone machinery rather than HSP-16.1's ATP-independent holdase sequestration. Supporting Evidence: PMID:9305934 both wild-type and C-terminally-truncated HSP16-2 can function as molecular chaperones by suppressing the thermally-induced aggregation of citrate synthase |
| GO:0050829 defense response to Gram-negative bacterium | IGI PMID:16916933 Heat-shock transcription factor (HSF)-1 pathway required for... | KEEP AS NON CORE | Summary: Singh & Aballay found that HSF-1-dependent immunity to Gram-negative pathogens requires small and 90-kDa inducible HSPs. Reason: Genetic requirement for pathogen resistance downstream of HSF-1; it reflects the general cytoprotective chaperone role rather than a specific defense mechanism. Abstract-only in cache; the curator's IGI is accepted as non-core. Supporting Evidence: PMID:16916933 The HSF-1 defense response is independent of the p38 MAPK/PMK-1 pathway and requires a system of chaperones including small and 90-kDa inducible HS proteins. |
| GO:0140309 unfolded protein holdase activity | ISS GO_REF:0000024 | MODIFY | Summary: Curator ISS transfer of unfolded protein holdase activity from a characterized sHSP. Reason: HSP-16.1 is an alpha-crystallin-domain sHSP and its close paralogue HSP-16.2 suppresses thermal aggregation of citrate synthase in vitro, so ATP-independent holdase activity is well supported. However GO:0140309 retains a carrier definition (escort to an acceptor molecule or location), which has not been shown. Following the hsp-16.2 review and go-ontology#30552, the replacement is the proposed holdase chaperone activity NTR. Proposed replacements: holdase chaperone activity Supporting Evidence: PMID:9305934 both wild-type and C-terminally-truncated HSP16-2 can function as molecular chaperones by suppressing the thermally-induced aggregation of citrate synthase PMID:2632349 These hsps show extensive sequence identity with the small hsps of Drosophila, as well as with mammalian alpha-crystallins. |
| GO:0140309 unfolded protein holdase activity | ISS PMID:4033652 Locus encoding a family of small heat shock genes in Caenorh... | MODIFY | Summary: ISS annotation citing the sequencing paper for the hsp16-1/hsp16-48 locus, which established homology of these genes to the small HSP / alpha-crystallin family. Reason: The sequence-similarity inference of holdase function is sound, but GO:0140309 keeps a carrier-specific definition; replace with the proposed holdase chaperone activity NTR as for the other sHSP rows. Proposed replacements: holdase chaperone activity Supporting Evidence: PMID:4033652 The genes coding for hsp 16-48, previously identified by cDNA cloning, and for another 16-kilodalton heat shock protein designated hsp16-1 were characterized by DNA sequencing. PMID:9305934 both wild-type and C-terminally-truncated HSP16-2 can function as molecular chaperones by suppressing the thermally-induced aggregation of citrate synthase |
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Download this section (compressed HTML)Q: Do HSP-16.1/16.2 (one subclass) and HSP-16.41/16.48 (the other subclass) form mixed oligomers in vivo, and do they differ in client range?
Q: Does the HSP-16 family hand clients to the inducible HSP70s (HSP-70, F44E5.4/5) for refolding, or primarily route them to sequestration/degradation?
Q: How does Golgi-localized HSP-16.1 cooperate with PMR-1 mechanistically - does it chaperone PMR-1 itself under heat stress?
Experiment: Purify recombinant HSP-16.1 and test ATP-independent suppression of thermal aggregation of model clients (citrate synthase, luciferase), alone and with HSP-70 + DNJ-13 to measure hand-off refolding.
Hypothesis: HSP-16.1 is an ATP-independent holdase whose bound clients can be refolded by the worm HSP70/HSP40 system.
hsp-16.11 encodes a 16-kD heat shock protein (HSP) that is a member of the hsp16/hsp20/alphaB-crystallin (HSP16) family of heat shock proteins, and that is identical to the protein encoded by hsp-16.1; hsp-16.11 expression is induced in response to heat shock or other environmental stresses; HSP-16.11 is likely to function as passive ligand temporarily preventing unfolded proteins from aggregating; HSP-16.11 has been shown to interact with intracellular human beta amyloid peptide, a primary component of the extracellular plaques found in Alzheimer's disease.
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